Novel bretylium compositions and kits and their use in preventing and treating cardiovascular conditions

ABSTRACT

The present invention is directed to novel pharmaceutical combinations including compositions and kits comprising bretylium as the active ingredient, as well as methods for preventing and/or treating conditions related to the cardiovascular system using such novel pharmaceutical combinations.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. ProvisionalApplication Serial No. 60/394,953, filed Jul. 10, 2002, and U.S.Provisional Application Serial No. 60/329,447, filed Oct. 15, 2001, andas a continuation-in-part of U.S. patent application Ser. No.09/869,940, filed Jul. 9, 2001, which is a 371 U.S. National Applicationof PCT/US00/00350, filed Jan. 6, 2000, which claims the benefit of U.S.Provisional Application Serial No. 60/116,567, filed Jan. 21, 1999 andU.S. Provisional Application Serial No. 60/115,143, filed Jan. 8, 1999.The entire texts of U.S. Provisional Application Serial No. 60/394,953,U.S. Provisional Application Serial No. 60/329,447, U.S. patentapplication Ser. No. 09/869,940, International ApplicationPCT/US00/00350, U.S. Provisional Application Serial No. 60/116,567 andU.S. Provisional Application Serial No. 60/115,143 are herebyincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

[0002] This invention relates to novel compositions and kits comprisinga pharmaceutically active quaternary ammonium cation such as bretyliumand a facilitating anion with or without other active agents such as,for example, a β-receptor blocker. This invention also relates to theuse of such compositions and kits to prevent and/or treat variouscardiovascular conditions.

BACKGROUND OF THE INVENTION

[0003] A variety of quaternary ammonium salts are pharmaceuticallyactive.

[0004] Bretylium tosylate 1 (also known as2-bromobenzylethyldimethylammonium p-toluenesulfonate) has thestructure:

[0005] It is a known Class III antiarrhythmic agent and an adrenergicblocking agent. The bretylium cation of this compound is reported todirectly modify the electrical properties of the myocardium. It also isreported to depress adrenergic neural transmission by blocking neuronalnorepinephrine release and re-uptake. Bretylium tosylate consequentlyhas been used worldwide to suppress life-threatening ventriculartachyarrhythmias, such as ventricular tachycardia and fibrillation.Bacaner (in U.S. Reissue Pat. No. 29,618, incorporated herein byreference) discloses suppressing cardiac ventricular fibrillation andcardiac arrhythmias generally by administering bretylium tosylate.Similarly, Bacaner (in U.S. Pat. No. 3,911,125, incorporated herein byreference) discloses treating angina pectoris, treating coronaryinsufficiency, and preventing myocardial infarction by administeringbretylium tosylate and bethanidine sulfate.

[0006] Bretylium is the only known drug that can induce the phenomenonof spontaneous defibrillation in large hearts (dog and man). In dogstreated with bretylium, electrically induced ventricular fibrillation bysuperthreshold shocks persisting for as long as two minutes is often notsustained because spontaneous defibrillation to sinus rhythm occursrepeatedly. Non-sustained ventricular fibrillation has also beenobserved in bretylium-treated dogs and humans subjected to coronaryartery legation. This phenomenon has also been reported in patientsreceiving bretylium treatment.

[0007] Unformulated bretylium tosylate exhibits poor and unpredictableabsorption into the bloodstream when orally ingested. Thus, oraladministration of bretylium tosylate alone is generally unsuitable fortreating heart conditions and has not been approved by the FDA becauseof poor and unpredictable tablet absorption. Accordingly, bretyliumtosylate is instead usually administered parenterally in the form of aninjectable solution. This mode of administration, however, isinconvenient and painful, particularly for chronic administration, andslow in onset of therapeutic action because bretylium tosylate has poorlipid solubility and difficulty crossing capillary and heart membranes.

[0008] Administration of bretylium tosylate (or other quaternaryammonium compounds) may also result in severely reduced ambulation in arecipient due to a sharp drop in blood pressure on assuming the uprightposition, resulting in dizziness and loss of consciousness. The severityof this side-effect, however, can be reduced (and the therapeuticeffects of the bretylium cation can be enhanced) by administering atricyclic anti-depressant agent (e.g., protriptyline, mazindol,amitriptyline, nortriptyline, or desipramine) with the bretyliumtosylate, as disclosed by Bacaner in U.S. Pat. No. 5,036,106.

[0009] A number of studies on the bioavailability of bretylium tosylatehave been described in the literature. Most of these studies, however,have primarily focused on parenteral, rectal, and other non-ingestedcompositions comprising bretylium tosylate. Most also involve theadministration of bretylium tosylate compositions under alkalineconditions.

[0010] Neubert et al. (in Ion Pair Approach of Bretylium, Pharm. Ind.54, Nr. 4 (1992)) disclose a series of experiments in which bretyliumtosylate was studied in the presence of saccharin, dodecylsulfate, orhexylsalicylate anions. The partition coefficient for the bretylium ionin the presence of these anions was measured using an alkaline (pH=7.2)n-octanol/buffer system and using an alkaline (pH=7.2) absorption modelsystem employing an artificial lipid membrane. Bretylium absorption invivo was also measured in rabbits receiving the bretylium tosylate incombination with these anions by i.v. injection (an i.v. injection ofbretylium tosylate in Sorensen phosphate buffer (pH=7.2), together withan i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphatebuffer (pH=7.2)) or rectal administration.

[0011] Neubert et al. (in Influence of Lipophilic Counter Ions on theTransport of Ionizable Hydrophilic Drugs, J. Pharm. Pharmacol. 1991, 43:204-206) disclose a series of experiments on the influence of thecounterions hydroxynaphthoate, naphthylsulphonate, adamantoate,desoxycholate, dehydrocholate, octanoate, decanoate, dodecanoate,hexadecanoate, and hexylsalicylate on the transport of bretylium usingan alkaline (pH=7.2) absorption model system. It was reported that theuse of hydroxynaphthoate, adamantoate, desoxycholate, or dehydrocholatecounterions resulted in minimal or no increase in bretylium transportacross the membrane. No therapeutic or electrophysiologic action isdisclosed.

[0012] Neubert et al. (in Drug Permeation Through Artificial LipoidMembranes, Pharmazie 42 (1987), H. 5) evaluated the effect of alkylatedderivatives of salicylic acid, particularly hexylsalicylic acid, on thepartition and transport of ionized basic drugs including bretyliumtosylate using lipophilic membranes in alkaline (pH=7.2) lipoid membranemodels.

[0013] Hartl et al. (in Influence of the Ion-Pair-Formation of Bretyliumand Hexylsalicylic Acid on Their Influence on Blood Plasma Levels inDogs, Pharmazie 45 (1990), H. 4) report an improvement in biologicalbretylium levels in dog plasma when a bretylium-tosylate/hexylsalicylicacid combination was administered to dogs by i.v. injection (an i.v.injection of bretylium tosylate in Sorensen phosphate buffer (pH=7.2),together with an i.v. injection of hexylsalicylic acid inethanol/Sorensen phosphate buffer (pH=7.2)). Hartl et al., however, donot discuss how to improve the bretylium level in the myocardium of theheart or the therapeutic effects of doing so or inducing sympatheticblockade.

[0014] Neubert et al. (in Influence of the Ion-Pair-Formation on thePharmacokinetic Properties of Drugs (Part 4), Pharmazie 43 (1988), H.12) report a series of experiments to determine the pharmacokineticparameters of bretylium tosylate administered in combination withhexylsalicylic acid in rabbits by i.v. injection or rectally. Notherapeutic or electrophysiologic action is disclosed, nor is there anyreference to oral administration.

[0015] Amlacher et al. (in Influence of Ion-Pair Formation on thePharmacokinetic Properties of Drugs, J. Pharm. Pharmacol. 1991, 43:794-797) disclose a series of experiments to measure the partitioncoefficients for the bretylium ion in the presence of salicylic acidusing an alkaline (pH=7.2) n-octanol/buffer system. Bretylium absorptionin vivo was also measured in rabbits receiving an i.v. injection ofbretylium tosylate in Sorensen phosphate buffer (pH=7.2), together withan i.v. injection of hexylsalicylic acid in ethanol/Sorensen phosphatebuffer (pH=7.2).

[0016] Neubert et al. (in Influence of the Ion-Pair-Formation on thePharmacokinetic Properties of Drugs (Part 5), Pharmazie 44 (1989), H. 9)disclose a series of experiments on the effect of ion-pair formation onthe elimination of bretylium and hexylsalicylic acid in rats. In theseexperiments, the rats received an i.v. injection of bretylium tosylatein Sorensen phosphate buffer (pH=7.2), together with an i.v. injectionof hexylsalicylic acid in ethanol/Sorensen phosphate buffer (pH=7.2)and, in some instances, an oral dose of cholestyramine. Neubert et al.concluded that the pharmacokinetic parameters of bretylium were notinfluenced by hexylsalicylic acid.

[0017] Cho (in WO 87/05505) discloses compositions comprising particlesconsisting essentially of a solid emulsifying agent and a surfactant, abiologically active proteinaceous material bound to the surface of theparticles, and a lipid coating surrounding such particles. While Cho isprimarily directed to pharmaceutical compositions comprising insulin, hedoes state generally that other pharmaceutical agents, such as bretyliumtosylate, could be employed. Additional ingredients in the compositionare described to include, among others, sodium lauryl sulfate (as asurfactant), sodium bicarbonate, and citric acid.

[0018] Stanley et al. (in U.S. Pat. Nos. 5,288,497 and 5,288,498)disclose a dissolvable or non-dissolvable drug containing matrix formfor administering a drug for absorption through the mucosal tissues ofthe mouth, pharynx, and esophagus. Stanley et al. identify a large groupof active drugs that can be administered buccally in accordance with theinvention. These references further disclose a variety of additionalingredients that can be included in the matrix including, among others,sodium lauryl sulfate and sodium dodecyl sulfate (as “permeationenhancers”) and buffering systems (to adjust salival pH). Although theStanley references list bretylium tosylate as one of the drugs that canbe administered in this manner, bretylium tosylate is very bitter andtoo unpalatable for human consumption by this mode of administration.

[0019] Finally, Bacaner et al. (in “Synergistic Action of Bretylium WithLow Doses Of Propranolol Renders The Canine Heart Virtually InvulnerableTo Sustained Ventricular Fibrillation”, Circulation, Supp. IV, page 111(1987)) disclose a synergistic enhancement in the onset and magnitude ofthe anti-fibrillatory action caused by bretylium tosylate when a small,non-β-blocking dosage of propranolol is added to a bretylium tosylatebolus injected into dogs. This synergism also has been demonstrated withother β-blocking drugs (sotalol, esmolol, metoprolol and carvedilol).

SUMMARY OF THE INVENTION

[0020] This invention provides, in part, novel pharmaceuticalcompositions and kits which may be administered to prevent and/or treatmedical conditions related to the cardiovascular system. Thesecompositions and kits have been found to be particularly suitable fororal administration, although they also have been found to be generallyuseful when administered parenterally. In addition, they often tend toexhibit superior activity, time for onset of action, potency, safety,and/or therapeutic effectiveness relative to conventionally usedquaternary ammonium formulations (particularly previously-tried oralformulations such as bretylium tosylate). In many instances, thecompositions and kits of this invention are especially advantageousbecause they may be self-administered as needed (for example, at aperson's residence or place of work to prevent sudden cardiac deathand/or non-fatal myocardial infarction) without the assistance of ahealth care professional. As defined herein, the term “composition”refers to a single compound or a mixture of compounds. A “kit,” incontrast, refers collectively to therapeutic ingredients which are inthe form of at least two separate, discrete sources that areindependently administered (whether jointly or at different times).

[0021] Briefly, therefore, this invention is directed to apharmaceutical combination useful for preventing and/or treating acardiovascular condition. The pharmaceutical combination comprises abretylium cation or a source of a bretylium cation; an acetylsalicylateanion or a source of an acetylsalicylate anion; and a β-receptor blockeror a source of a β-receptor blocker. The combination is furthercharacterized in that the acetylsalicylate anion comprises a compound ofthe structure:

[0022] wherein

[0023] R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl andR¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl. Further, thebretylium cation or the source of the bretylium cation, theacetylsalicylate anion or the source of the acetylsalicylate anion, andthe β-receptor blocker or the source of the β-receptor blocker togetherare present in the pharmaceutical combination in a therapeuticallyeffective amount.

[0024] In a preferred embodiment, the pharmaceutical combinationcomprises comprises a pharmaceutical composition comprising a bretyliumcation, an acetylsalicylate anion and a β-receptor blocker. Theacetylsalicylate anion of the composition comprises a compound of thestructure:

[0025] wherein

[0026] R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl andR¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl. Further, thebretylium cation, the acetylsalicylate anion and the β-receptor blockertogether are present in the pharmaceutical composition in atherapeutically effective amount.

[0027] In another preferred embodiment, the pharmaceutical combinationcomprises a pharmaceutical kit comprising a source of a bretyliumcation, a source of a β-receptor blocker, and a source of anacetylsalicylate anion. The acetylsalicylate anion of the pharmaceuticalkit comprises a compound of the structure:

[0028] wherein

[0029] R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl andR¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl. The kit isfurther characterized in that the bretylium cation, the β-receptorblocker and the acetylsalicylate anion are present in the pharmaceuticalkit in a therapeutically effective amount (i.e., the bretylium cation,the β-receptor blocker and the acetylsalicylate anion are present in thekit in amounts such that their combination is therapeutically effectiveafter the components of the kit are administered).

[0030] The present invention is further directed to a pharmaceuticalcombination useful for preventing and/or treating a cardiovascularcondition. The pharmaceutical combination comprises a bretylium cationor a source of a bretylium cation; acetylsalicylic acid or an alkalimetal salt of acetylsalicylic acid; and a β-receptor blocker or a sourceof a β-receptor blocker. The pharmaceutical combination is characterizedin that the pharmaceutical combination is suitable for oral ingestion;and the bretylium cation or the source of a bretylium cation, theacetylsalicylic acid or the alkali metal salt of acetylsalicylic acid,and the P-receptor blocker or the source of a β-receptor blockertogether are present in the pharmaceutical combination in atherapeutically effective amount.

[0031] In a preferred embodiment, the pharmaceutical combinationcomprises a pharmaceutical composition comprising a bretylium cation,acetylsalicylic acid or an alkali metal salt of acetylsalicylic acid anda β-receptor blocker. The pharmaceutical composition is suitable fororal ingestion and further characterized in that the bretylium cation,the acetylsalicylic acid or alkali metal salt of acetylsalicylic acidand the β-receptor blocker together are present in the pharmaceuticalcomposition in a therapeutically effective amount.

[0032] In another preferred embodiment, the pharmaceutical combinationcomprises a pharmaceutical kit comprising a source of a bretyliumcation, acetylsalicylic acid or an alkali metal salt of acetylsalicylicacid and a source of a β-receptor blocker. The source of the bretyliumcation, the source of the acetylsalicylate anion and the source of theβ-receptor blocker are, in combination, suitable for oral ingestion. Thekit is further characterized in that the bretylium cation, theacetylsalicylic acid or alkali metal salt of acetylsalicylic acid andthe β-receptor blocker are present in the kit in a therapeuticallyeffective amount.

[0033] The present invention is further directed to a pharmaceuticalcomposition comprising from about 10% to about 40% by weight bretyliumcation, from about 5% to about 40% by weight acetylsalicylate anion, andfrom about 0.1% to about 1.0% by weight β-receptor blocker. In apreferred embodiment, the β-receptor blocker of the pharmaceuticalcomposition comprises propranolol. In another preferred embodiment, theβ-receptor blocker of the pharmaceutical composition comprisesmetoprolol. In still another preferred embodiment, the pharmaceuticalcomposition further comprises from about 30% to about 75% by weightneutralizing agent, preferably a mono-, di-, or poly-amino sugar such asmethyl glucamine.

[0034] Still further, the present invention is directed to apharmaceutical composition comprising a bretylium cation, anacetylsalicylate anion, a β-receptor blocker and a neutralizing agent.In a preferred embodiment, the β-receptor blocker of the pharmaceuticalcomposition comprises propranolol. In another preferred embodiment, theβ-receptor blocker of the pharmaceutical composition comprisesmetoprolol. Preferably, the composition is in a form comprising asolution or a suspension, more preferably in a form suitable foradministration as an emergency resuscitation solution for treatingsudden cardiac arrest.

[0035] Still further, the present invention is directed to a method fortreating sudden cardiac arrest in a human or animal patient. The methodcomprises administering a pharmaceutical composition comprising abretylium cation, an acetylsalicylate anion, a β-receptor blocker and aneutralizing agent to a subject in need thereof. In a preferredembodiment, the pharmaceutical composition comprises a bretylium cation,an acetylsalicylate anion, propranolol and methyl glucamine. In anotherpreferred embodiment, the pharmaceutical composition comprises abretylium cation, an acetylsalicylate anion, metoprolol and methylglucamine.

[0036] Still further, the present invention is directed to a method forpreventing and/or treating a cardiovascular condition. The methodcomprises administering a pharmaceutical combination of the presentinvention to a subject in need thereof. More particularly, thepharmaceutical combinations of the present invention can be administeredto: (1) prevent sudden cardiac death; (2) prevent and/or treatmyocardial infarction; (3) prevent and/or treat congestive heartfailure; (4) prevent and/or treat ventricular fibrillation; (5) preventand/or treat ventricular arrhythmia; (6) prevent and/or treatventricular tachycardia; (7) prevent and/or treat ventricular prematureheartbeats; (8) prevent and/or treat atrioventricular dissociation; (9)prevent and/or treat multifocal ectopic beats; (10) prevent and/or treatpremature ventricular extrasystoles; (11) prevent and/or treat bigeminalrhythm; (12) prevent and/or treat trigeminal rhythm; (13) prevent and/ortreat angina pectoris; (14) prevent and/or treat coronary insufficiency;(15) prevent and/or treat sympathetically induced pain; (16) restoreand/or maintain normal sinus rhythm; (17) increase the effectiveventricular refractory period; (18) increase the sinus automaticitytransiently; (19) prolong the Purkinje action potential duration; (20)induce post-ganglionic sympathetic blockade; (21) block the sympatheticnervous system; (22) reduce vascular impedance; (23) increase theventricular fibrillation threshold; (24) prolong the action potentialduration of cardiac cells; and/or (25) prevent or treat congestive heartfailure or coronary spasm.

[0037] The present invention is further directed to a method forpreventing and/or treating atrial fibrillation. The method comprisesadministering an anti-fibrillation pharmaceutical composition to apatient susceptible to atrial fibrillation wherein the compositioncomprises a salt of bretylium, acetylsalicylic acid or an alkali metalsalt of acetylsalicylic acid and a β-receptor blocker. In a preferredembodiment, the anti-fibrillation composition comprises a salt ofbretylium, acetylsalicylic acid or an alkali metal salt thereof andpropranolol or metoprolol.

[0038] The present invention is still further directed to apharmaceutical combination comprising bretylium and bethanidine sulfate.The bethanidine sulfate acts synergistically to intensify theanti-fibrillatory action of bretylium as well as the sympatheticblocking effect of bretylium. This combination increases theanti-adrenergic effect of bretylium alone when and if tolerance to thiseffect of bretylium develops. This may also be useful in treatinghypertension, angina pectoris and lowering vascular impedence.

[0039] The present invention is still further directed to a method fortreating and/or preventing shock in a human or animal patient. Themethod comprises administering a pharmaceutical combination comprising abretylium cation or a source of a bretylium cation, a facilitating anionor a source of a facilitating anion, and an anti-hypotensive agentand/or a β-receptor blocker or a source of an anti-hypotensive agentand/or a β-receptor blocker to a human or animal patient in needthereof. The pharmaceutical combination is characterized in that thefacilitating anion is less hydrophilic than a tosylate anion; and thebretylium cation or the source of the bretylium cation, the facilitatinganion or the source of the facilitating anion, and the anti-hypotensiveagent and/or the β-receptor blocker or the source of theanti-hypotensive agent and/or the β-receptor blocker together arepresent in said pharmaceutical combination in a therapeuticallyeffective amount. Preferably, the pharmaceutical combination isadministered for the treatment and/or prevention of septic shock,hemorrhagic shock, cardiogenic shock or hypovolemic shock.

[0040] It is important to note that any of the pharmaceuticalcompositions or kits of the present invention may also preferablycomprise one or more of the following, alone or in any appropriatecombination: a neutralizing agent, a buffering agent, ananti-hypotensive agent and/or a β-receptor blocker. Here, the bretyliumcation, the facilitating anion, the neutralizing agent, the bufferingagent, the anti-hypotensive agent and/or the β-receptor blocker togetherare present in the pharmaceutical composition in a therapeuticallyeffective amount (or, in the case of a kit, the bretylium cation, thefacilitating anion, the neutralizing agent, the buffering agent, theanti-hypotensive agent and/or the β-receptor blocker are present in thekit in amounts such that their combination is therapeutically effectiveafter they are administered). For kits, the preferred order ofadministration would be to administer the neutralizing agent and thebuffer first to adjust the pH of the stomach. A facilitating anion mayor may not be added along with the neutralizing agent and the buffer.For example, prior to the administration of a salt containing abretylium cation and a facilitating anion of the invention, it would bepreferred to administer a commercially available Alka Seltzer®, whichgenerally contains a neutralizing agent, a citric buffer and aspirin.However, those skilled in the art will appreciate that the order ofapplication of the components in the kit need not be in any specificorder.

[0041] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

BRIEF DESCRIPTION OF THE FIGURES

[0042]FIG. 1 is an electrocardiogram of a dog showing the effect onatrial fibrillation that was observed after administering via injectiona composition containing roughly: (a) 15 mg of bretylium tosylate per kgof dog, and (b) 6.5 mg of aspirin per kg of dog.

[0043]FIG. 2 is an electrocardiogram of a dog chosen as a control andshows normal sinus rhythm.

[0044]FIG. 3 is an electrocardiogram of a dog taken immediately afterpainting a dilute solution of aconitine on the surface of the rightatrium.

[0045]FIG. 4 shows the electrocardiogram of the dog with sustainedatrial fibrillation after painting with aconitine. After approximately40 seconds, spontaneous sustained atrial fibrillation was induced aftera short burst of atrial tachycardia.

[0046]FIG. 5 shows continued, sustained atrial fibrillation lasting 53minutes after application of aconitine to the right atrium.

[0047]FIG. 6 shows sustained atrial fibrillation in the dog for 40minutes, then a 15 mg/kg dose of bretylium lauryl sulfate salt was givenorally after observing 53 minutes of atrial fibrillation.

[0048]FIG. 7 shows that 19 minutes and 24 seconds after administrationof oral bretylium lauryl sulfate salt, the dog spontaneously came out ofatrial fibrillation and regained normal sinus rhythm.

[0049]FIG. 8 shows that the dog maintained a normal sinus rhythm 46minutes after administration of the bretylium lauryl sulfate salt, evenafter attempts to reinitiate atrial fibrillation with electricalstimulation.

[0050]FIG. 9 demonstrates that ventricular or atrial fibrillation didnot occur in a dog despite maximum electrical stimulation (50 milliamps)after administration of Bretylium Salicylate.

[0051]FIG. 10 demonstrates that ventricular atrial fibrillation did notoccur in a dog despite maximum electrical stimulation (50 milliamps)after administration of Bretylium and Aspirin.

[0052]FIG. 11 demonstrates that ventricular or atrial fibrillation didnot occur in a dog despite maximum electrical stimulation (50 milliamps)after administration of Bretylium Lauryl Sulfate.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0053] Past efforts to orally administer bretylium drugs have failed dueto poor and/or unpredictable absorption in the gastrointestinal tract.For example, when conventional bretylium-containing drugs (particularlyunformulated bretylium tosylate) have been administered orally, theactive component of the drugs (i.e., the bretylium cation) has typicallyexhibited poor and/or unpredictable uptake in the gastrointestinaltract. This, along with the orthostatic hypotension side-effect of thesedrugs, have made oral self-administration difficult, thereby largelylimiting the use of the drugs to parenteral administration in clinicalemergencies when other antiarrhythmic agents have failed.

[0054] Unlike previous oral formulations of bretylium compounds, such asbretylium tosylate, the pharmaceutical compositions and kits of thepresent invention are uniquely adapted for oral administration. Inaddition, they often tend to exhibit superior activity, time for onsetof action, potency, safety, and/or therapeutic effectiveness relative toconventionally used quaternary ammonium formulations (particularlypreviously-tried oral formulations such as bretylium tosylate). In manyinstances, the compositions and kits of this invention are especiallyadvantageous because they may be self-administered as needed (forexample, at a person's residence or place of work to prevent suddencardiac death and/or non-fatal myocardial infarction) without theassistance of a health care professional.

[0055] Hypothesized Mechanisms of Action

[0056] Bretylium ion, if taken internally, must pass through theintestine to the bloodstream, and from there, to the targeted hearttissue. Bretylium ion may be released internally from the dissolution ofbretylium tosylate, its most common commercially available form.Macroscopic quantities of ions can only be transferred from one phase toanother in neutral combinations. Otherwise, the phases becomeelectrically charged. The uncompensated transfer of an electricallycharged ion is energetically very unfavorable. Bretylium saltsdissociate to release the quaternary cations in solution. In accordancewith the invention, it has been discovered that these therapeuticcations can be transferred across a lipid barrier when in the company ofone or several facilitating anions. Use of bretylium with a much lesshydrophilic or actually hydrophobic facilitating anion or anions resultsin improved and increased transfer rates across the biological membranesof interest.

[0057] In the aqueous contents of the gastrointestinal tract(particularly the stomach and intestine), orally administered bretyliumtosylate dissociates to the bretylium cation and the tosylate anion (orthe other anion in the bretylium-cation source). To provide the desiredtherapeutic effect, however, the bretylium cation must be absorbed fromthe aqueous contents of the gastrointestinal tract through the lipidphase mucosa of the gastrointestinal tract into the blood, and thentransferred from the blood to the target cells (typically (a) thesympathetic ganglia and their postganglionic adrenergic neurons, and (b)cardiac cells). Absorption of the bretylium cation from thegastrointestinal tract into the blood requires that the hydrophilicbretylium cation cross the lipophilic lipid phase boundary of thegastrointestinal tract. It has been discovered that this absorption (orcrossing of the lipid phase boundary) can be improved if the bretyliumcation is combined with one or more suitable types of anions (i.e.,facilitating anions) resulting in a bretylium-cation/facilitating-anioncombination that is more lipophilic, or less hydrophilic, than bretyliumtosylate. Hydrophilicity of an anion is reduced either by spreading thenegative charge over a number of atoms, or by attaching uncharged,weakly polar residues, such as alkyl groups, or both.

[0058] It is hypothesized that the bretylium cation and the facilitatinganion in the gastrointestinal tract can exist in the form of separateions, ion pairs, micelles, or otherwise. When the bretylium cationenters the lipid phase, however, it does so as abretylium-cation/facilitating-anion combination in the form of ion pairsand/or higher ion aggregates, such as inverse micelles. Thesebretylium-cation/facilitating-anion combinations possess a neutral orsubstantially neutral charge. In addition, thesebretylium-cation/facilitating-anion combinations are more lipophilic, orless hydrophilic, than bretylium tosylate. A partition coefficient canbe utilized to predict how well the facilitating anion will work incomparison to an anion coupled with the quaternary ammonium cation.

[0059] It is believed that the anions of the invention should have awidespread charge distribution over the molecule, such that when itaggregates with the quaternary ammonium cation, the combination has weakaffinity to water (i.e., the combination has a slight affinity to water,little affinity to water, or essentially no affinity to water) and/orthe combination is non-polar. One such anion would be 2,4,6trinitrophenol, however, this anion is known to be toxic. Non-toxicanions capable of forming about aggregates having a low affinity forwater are the focus of this invention.

[0060] When the bretylium cation and facilitating anion are ingested andionized in the absence of a neutralizing agent, hydrochloric acidpresent in the stomach converts a portion of the ionized anions to thecorresponding conjugate acid of the anions, which is then largelyabsorbed by the lipid mucosa in the intestine. As these anions areconverted to their conjugate acid form and absorbed, additional anionsare then converted to their conjugate acid, and, in turn, absorbed inthe intestine. If the anions are too readily converted to theirconjugate acid form and/or the pH of the gastrointestinal tract is toolow, the hydrophilic chloride anions will effectively be the only anionsavailable for combination with the bretylium cation (if tosylate anionsare also present, they too will be converted into their conjugate acid,p-toluenesulfonic acid, and, in turn, absorbed in the intestine).Because the bretylium cation cannot be spacially separated from acounterion, and the chloride anions are not readily removed from theaqueous phase, the bretylium cation remains in the aqueous fluid of thestomach and intestine and is ultimately not absorbed. To reduce oreliminate this problem, a neutralizing agent may be administered toincrease the pH of the stomach. It is believed that such a pH increaseenhances the absorption of the bretylium cation by reducing the amountof the facilitating anion that is converted to its conjugate acid suchthat a larger portion of the facilitating anion remains available toform the bretylium-cation/facilitating-anion combination.

[0061] It is further hypothesized that the compositions and kits of thisinvention not only enhance the absorption of the bretylium cation fromthe gastrointestinal tract into the blood, but also enhance thepermeation of the bretylium cation from the blood through the capillarywalls and the target tissue (the target tissue being myocardial cells,etc.). For example, the di(2-ethylhexyl)sulfosuccinate anion promotesthe formation of water-in-oil emulsions. Such emulsions generallyconsist of droplets having an aqueous core surrounded bydi(2-ethylhexyl)sulfosuccinate anions, with the anionic sulfonate groupsdirected inwardly toward the core center and the hydrocarbon groupsdirected outwardly from the core, in contact with the oil or lipid bulkphase. The core typically contains a sufficient number of cations toprovide the whole assembly with a neutral charge. Such emulsion dropletsgenerally have a radius ranging from about 10×10⁻⁸ cm to about 30×10⁻⁸cm. Because the typical cell wall has a hydrophobic core bounded by afilm having a thickness of about 30×10⁻⁸ cm, a closed emulsion dropletmay not form in such a film since the film is too thin to surround thedroplet. It is hypothesized, however, that a short cylinder ofdi(2-ethylhexyl)sulfosuccinate anions may form instead, with the anionicsulfonate groups directed inwardly toward an aqueous core and theirhydrocarbon groups directed outwardly toward the lipid of the cell wall,and with the two ends of the cylinder open. One of the open ends isdirected outward and the other is directed into the cell. Such astructure would act as a conduit through which the bretylium cationcould reach the interior of target cells.

[0062] It is additionally hypothesized that these emulsion dropletsand/or cylinders also may form in the mucosa of the intestine, withbretylium acting as the neutralizing cation, thereby promoting theabsorption of the bretylium cation through the intestinal walls in asimilar manner as in the walls of the target cells.

[0063] The Compositions of the Present Invention

[0064] The compositions of the present invention comprise a bretyliumcation and a facilitating anion and, optionally, one or moreneutralizing agent(s), buffering agent(s), anti-hypotensive agent(s)and/or a β-receptor blocker. Generally, the composition of the presentinvention comprises from about 1% to about 60% bretylium cation and fromabout 1% to about 60% facilitating anion. Preferably, the compositioncomprises from about 1% to about 90% of a salt of the bretylium cationand facilitating anion. Optionally and preferably, the composition ofthe present invention may also include from about 0.01% to about 75%neutralizing agent, from about 0.01% to about 30% buffering agent, fromabout 0.0% to about 0.5% anti-hypotensive agent and from about 0.0% toabout 1.0% β-receptor blocker, with any combination of the precedingconsidered part of the invention. For example, in a preferredembodiment, a composition of the present invention comprises from about10% to about 60% bretylium cation, from about 5% to about 60%facilitating anion, from about 30% to about 75% neutralizing agent andfrom about 0.01% to about 1.0% β-receptor blocker. In another preferredembodiment, the compositions and kits of the present invention comprisefrom about 10% to about 40% by weight bretylium cation, from about 5% toabout 30% by weight facilitating anion, from about 40% to about 70% byweight neutralizing agent and from about 0.1% to about 1.0% by weightβ-receptor blocker.

[0065] Stated another way, the composition of the present invention maybe described as a 1.0 gm tablet comprising from about 1 to about 900 mgsalt of the bretylium cation and facilitating anion. Optionally andpreferably, the composition may also include from about 0.01 to about500 mg of neutralizing agent, from about 0.01 to about 300 mg ofbuffering agent, from about 0 to about 5 mg of anti-hypotensive agentand from about 0 to about 10 mg of β-receptor blocker with a remainderof the composition comprising fillers, disintegrants, binding agents,adhesives, wetting agents, lubricants, glidants, anti-adherents, entericcoatings, inert diluents and/or surface active/dispersing agents. Anycombination of the above is considered part of the invention.

[0066] Particularly preferred compositions fall within one of thefollowing categories:

[0067] (1) Compositions comprising a bretylium cation, a facilitatinganion, a neutralizing agent and preferably, a buffering agent.

[0068] (2) Compositions comprising a bretylium cation, a facilitatinganion, and an anti-hypotensive agent.

[0069] (3) Compositions comprising a bretylium cation, a facilitatinganion, a neutralizing agent, a buffering agent and an anti-hypotensiveagent.

[0070] (4) Compositions comprising a bretylium cation, a facilitatinganion, and a β-receptor blocker.

[0071] (5) Compositions comprising a bretylium cation, a facilitatinganion, an anti-hypotensive agent, and a β-receptor blocker.

[0072] (6) Compositions comprising a bretylium cation, a facilitatinganion, a neutralizing agent, and an anti-hypotensive agent. Here, it isespecially preferred for the compositions to also comprise a bufferingagent.

[0073] (7) Compositions comprising a bretylium cation, a facilitatinganion, a neutralizing agent, and a β-receptor blocker. Here, it isespecially preferred for the compositions to also comprise a bufferingagent.

[0074] (8) Compositions comprising a bretylium cation, a facilitatinganion, a neutralizing agent, an anti-hypotensive agent, and a β-receptorblocker. Here, it is especially preferred for the compositions and kitsto also comprise a buffering agent.

[0075] (9) Compositions comprising a bretylium cation, anacetylsalicylate anion and a β-receptor blocker.

[0076] (10) Compositions comprising a bretylium cation, aspirin (i.e.,“acetylsalicylic acid”) or an alkali metal salt of acetylsalicylic acidand a β-receptor blocker.

[0077] (11) Compositions comprising a bretylium cation, anacetylsalicylate anion, a β-receptor blocker and optionally ananti-hypotensive agent.

[0078] (12) Compositions comprising a bretylium cation and anacetylsalicylate anion.

[0079] (13) Compositions comprising a bretylium cation and at least oneβ-receptor blocker (particularly propranolol, atenolol, esmolol,metoprolol, labetalol, talinolol, timolol, acebutolol,dichloroisoproterenol, pronethalol, sotalol, oxprenolol, alprenolol,practolol, nadolol, pindolol, penbutolol or carvedilol) and/or combinedwith bethanidine sulfate to synergize anti-fibrillatory and sympatheticblocking actions of bretylium.

[0080] Kits of the Invention

[0081] The current invention includes the concept of a kit, wherein thebretylium cation of the invention may be provided as a salt of anon-facilitating anion (such as bromide or chloride) and thefacilitating anion may be provided as a salt of a non-quaternaryammonium salt (such as sodium or potassium). The kit may include suchitems as neutralizing agents, buffers, anti-hypotensive agents andβ-receptor blockers.

[0082] The bretylium cation, the neutralizing agent, the bufferingagent, the anti-hypotensive agent, and/or the β-receptor blocker and thefacilitating anion together are present in the kit in a therapeuticallyeffective amount such that their combination is therapeuticallyeffective after they are administered. The individual components (e.g.,the bretylium cation, the neutralizing agent, buffering agents,anti-hypotensives, etc.) may be any convenient combination ofcompositions in any convenient formulation such as pills, syrups,liquids or aerosols, and may be administered in any appropriate manner,e.g., parenterally, orally or by inhalation of an aerosol. Suchcompositions may include one or more of the individual components of theinvention and each kit may have multiple compositions in it.

[0083] Source of the Bretylium Cations

[0084] The compositions and kits of this invention may contain thebretylium cation in the form of a pharmaceutically acceptable materialthat either comprises the bretylium cation itself or is capable offorming the bretylium cation after being administered to the intendedrecipient (and, consequently, when a composition or kit is referred toherein as comprising the bretylium cation, it should be understood thatthe composition or kit may either comprise the bretylium cation itselfor be capable of forming the bretylium cation after being administeredto the intended recipient). Thus, for example, when intended for oraladministration, the pharmaceutically acceptable material should releasethe bretylium cation into the aqueous contents of the gastrointestinaltract. Suitable materials include, for example, pharmaceuticallyacceptable salts of the bretylium cation (e.g., bretylium tosylate,bretylium di(2-ethylhexyl) sulfosuccinate, or bretylium salicylate), andsolutions or suspensions comprising the bretylium cation. Pharmaceuticalgrade bretylium tosylate is commercially available from, for example,Ganes Chemicals, Inc., Carlstadt, N.J. Alternatively, bretylium tosylatemay be prepared, for example, by reacting o-bromobenzylethylmethylaminewith methyl tosylate, as discussed in U.S. Pat. No. 3,038,004.

[0085] When the material is a pharmaceutically acceptable salt otherthan bretylium tosylate, the anion of the salt preferably has little orno tendency to form a covalent compound with the bretylium cation. Suchsalts may be prepared, for example, by using a conventional doubledisplacement reaction, wherein a bretylium salt (e.g., bretyliumtosylate) is reacted with a suitable acid or alkali metal salt(preferably a sodium salt) of the desired anion.Bretylium-cation-containing materials, which have been approved by theFood and Drug Administration for use in other medicines or foods, aregenerally most preferred.

[0086] Source of the Facilitating Anion

[0087] The compositions and kits of this invention may contain thefacilitating anion in the form of a pharmaceutically acceptable materialthat either comprises the facilitating anion itself or is capable offorming the facilitating anion after being administered to the intendedrecipient (and, consequently, when a composition or kit is referred toherein as comprising a facilitating anion, it should be understood thatthe composition or kit may either comprise the facilitating anion itselfor be capable of forming the facilitating anion after being administeredto the intended recipient). It is preferred that the facilitating anionhave a weak affinity for water and/or be non-polar, and it isparticularly preferred for the facilitating anion to be less hydrophilicthan the tosylate anion. Such an anion, when ingested with the bretyliumcation (either in the form of a compound containing a salt of thebretylium cation and the facilitating anion, or separate salts of thebretylium cation and the facilitating anion), tends to formcation/facilitating-anion combinations capable of, for example, crossingthe lipid phase boundary of the gastrointestinal tract to enter thebloodstream, and crossing the lipid barriers of the capillary membranesand myocardial cell membranes of the heart. Preferably, the facilitatinganion forms bretylium cation/facilitating anion combinations having aneutral or substantially neutral charge. Such combinations are alsopreferably more lipophilic (or less hydrophilic) than bretyliumtosylate. Partition coefficient measurements can help predict whether aparticular anion will facilitate the transfer of the bretylium cation.Facilitating-anion-containing materials, which have been approved by theFood and Drug Administration for use in other medicines or foods, aregenerally most preferred.

[0088] It is particularly preferred for the facilitating anion to haveat least one of the following features:

[0089] (1) The facilitating anion is the conjugate base of an acidhaving a pK_(a) value of less than about 5, more preferably less thanabout 4, and still more preferably less than about 3. Where aneutralizing agent is not administered, it is preferred for thefacilitating anion to be the conjugate base of an acid having a pK_(a)value of less than about 1, more preferably less than about 0, and stillmore preferably less than about −1. Although the pK_(a) valuesassociated with suitable facilitating anions may be less than about −10,most suitable facilitating anions will have a pK_(a) value of about −10.

[0090] (2) The facilitating anion has a well-distributed charge toreduce its hydrophilicity. A particularly preferred example of such ananion is the salicylate anion.

[0091] (3) Alternatively, the facilitating anion comprises at least onealkyl group that comprises at least 10 carbon atoms. A preferred exampleof such an anion is the dodecylsulfate anion.

[0092] (4) The facilitating anion has an organic/aqueous phasedistribution constant (“K”) that is greater than the organic/aqueousphase distribution constant associated with the tosylate anion (i.e.,greater than about 320). In a particularly preferred embodiment, thefacilitating anion has a K value which is greater than about 500, morepreferably greater than about 700, still more preferably greater thanabout 800, and still even more preferably greater than about 1000.Although the K values associated with suitable facilitating anions maybe greater than about 10⁶, the most suitable facilitating anions have aK value which is less than about 10⁶. To determine the K value for aparticular anion, a small amount of methyltridecylammonium chloride(“Q⁺Cl⁻”) and a small amount of the methyltridecylammonium salt of theanion (“Q⁺X⁻”) are added to a mixture of water and octanol. The mixtureis allowed to separate, and the concentrations of the chloride ion andthe anion in each phase are then measured. The K value is calculatedusing the formula: K=[X⁻, oct.] [Cl⁻, aq.]/[X⁻, aq.] [Cl⁻, oct.],wherein the quantities in brackets are concentrations. The K value forthe salicylate anion, for example, is reported to be greater than 1000.A more extensive discussion of the procedure for determining K valuescan be found in, for example, C. J. Coetzee and H. Freisee, Anal. Chem.,Vol. 41, Page 1128 (1969) (incorporated herein by reference).

[0093] Examples of suitable facilitating anions include, but are notlimited to, the following:

R¹OSO₃ ⁻,

R²SO₃ ⁻,

[0094]

[0095] a pseudo-icosahedral carborane anion (CB₁₁H₁₂ ⁻), and

[0096] a substituted pseudo-icosahedral carborane anion.

[0097] In the above-formulas, R¹, R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and the substituent (or substituents) ofthe substituted pseudo-icosahedral carborane anion are independentlyhydrocarbyl or substituted hydrocarbyl; and R⁵ and R¹⁸ are independentlyhydrogen, hydrocarbyl, or substituted hydrocarbyl. In a particularlypreferred embodiment, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and the substituent (or substituents) of thesubstituted pseudo-icosahedral carborane anion are independentlyhydrocarbyl; and R¹⁸ is hydrogen. In such an embodiment, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R₁₃, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and thesubstituent (or substituents) of the substituted pseudo-icosahedralcarborane anion are preferably independently selected from the groupconsisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl,arylalkyl, arylalkenyl, or arylalkynyl. The preferred aryl is phenyl.The aryl moiety may be unsubstituted or substituted with one or moreradicals selected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, and cycloalkenyl.

[0098] In a preferred embodiment, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, and the substituent (orsubstituents) of the substituted pseudo-icosahedral carborane anion areindependently a residue of a fatty acid formed by removing a carboxylicacid group from the fatty acid.

[0099] In another preferred embodiment, the facilitating anion comprisesan anion selected from the group consisting of (C₁₀-C₃₀)alkylsulfateanions, (C₁₀-C₃₀)alkylsulfonate anions, (C₆-C₁₂)alkylsulfosuccinateanions, salicylate anions, (C₁-C₃₀)alkylsalicylate anions,(C₁₀-C₃₀)alkylphosphate anions, di(C₈-C₁₂)alkylphosphate anions,di(C₁₀-C₃₀)alkanoylphosphatidate anions, (C₈-C₂₂)alkylmaleate anions,di(C₄-C₁₂)alkylmaleate anions, α-keto (C₉-C₂₁)carboxylate anions,α-hydroxy (C₉-C₂₁)carboxylate anions, (C₁₂-C₂₂)alkylmalonate anions, and(C₁-C₁₈)alkylpseudo-icosahedral carborane anions.

[0100] Still more preferably, the facilitating anion comprises an anionselected from the group consisting of (C₁₀-C₃₀)alkylsulfate anions,(C₁₀-C₃₀)alkylsulfonate anions, (C₆-C₁₂)alkylsulfosuccinate anions,salicylate anions, (C₁₀-C₃₀)alkylphosphate anions,di(C₈-C₁₂)alkylphosphate anions, and di(C₈-C₂₂)alkanoylphosphatidateanions.

[0101] Still even more preferred facilitating anions comprise an anionselected from the group consisting of the di(2-ethylhexyl)sulfosuccinateanion 2; the salicylate anion 3; the di(2-ethylhexyl) phosphate anion 4;the lauryl sulfate anion 5; the hexadecylsulfonate anion 6; thedipalmitoyl phosphatidate anion 7; and the acetylsalicylate anion 8:

[0102] In a particularly preferred embodiment, the facilitating anion isthe di(2-ethylhexyl)sulfosuccinate anion 2. In another particularlypreferred embodiment, the facilitating anion is the salicylate anion 3.In yet another particularly preferred embodiment, the facilitating anionis the lauryl sulfate anion 5. In still a further particularly preferredembodiment, the facilitating anion is the acetylsalicylate anion 8. Ithas been found in accordance with this invention that these anions (andespecially the salicylate anion, the lauryl sulfate anion, and theacetylsalicylate anion), in general, tend to synergistically enhance thetherapeutic effects of the bretylium cation by, for example,synergistically increasing the ventricular fibrillation threshold andsynergistically prolonging the effective ventricular refractory period.

[0103] When intended for oral administration, the source of thefacilitating anion preferably is a pharmaceutically acceptable materialthat releases the facilitating anion into the aqueous contents of thegastrointestinal tract. Non-limiting examples of suitable facilitatinganion sources include the pharmaceutically acceptable salts of thefacilitating anion (e.g., the alkali metal salts, particularly thesodium salts, of the facilitating anion), and solutions or suspensionscomprising the facilitating anion. When the source is a salt, thecounterion paired with the facilitating anion preferably has little orno tendency to associate with the facilitating anion. Such salts may beprepared by conventional means from the conjugate acid of thefacilitating anion (e.g., reacting an appropriate base with theconjugate acid).

[0104] In one of the most preferred embodiments, the pharmaceuticalcomposition or kit contains the acetylsalicylate anion in the form ofacetylsalicylic acid (i.e., aspirin) or an alkali metal salt ofacetylsalicylic acid (e.g., a sodium, potassium, calcium or magnesiumsalt of acetylsalicylic acid). One reason for this particular preferencestems from the fact that in addition to enhancing the effects of thebretylium cation (apparently synergistically), the acetylsalicylateanion reduces or entirely blocks platelet aggregation (a common cause ofcardiac complications). Preferably, the acetylsalicylic acid or alkalimetal salt of acetylsalicylic acid is given prior to or concomitantlywith the administration of the bretylium. Although the acetylsalicylateanion can be provided in molar ratios under 1 (e.g., from about 0.5 to1), it is preferred to use at least a 1:1 molar ratio ofacetylsalicylate anion to bretylium cation, most preferably a slightmolar excess of acetylsalicylate anion (i.e., a molar ratio ofacetylsalicylate anion to bretylium cation of from about 1.1 to about1.5). For example, in a preferred embodiment of the present inventioncomprising a 1000 mg dosage of bretylium (i.e., 15 mg/kilo in a 70 kghuman), an 800 mg dosage of acetylsalicylic acid or alkali metal salt ofacetylsalicylic acid should preferably be applied.

[0105] Sodium di(2-ethylhexyl)sulfosuccinate is commercially availablefrom Aldrich Chemical Co., Milwaukee, Wis. Potassiumdi(2-ethylhexyl)sulfosuccinate can be prepared from the sodium salt byrecrystallization from aqueous solution in the presence of an excess ofpotassium chloride.

[0106] Salicylic acid and sodium salicylate are both commerciallyavailable from Aldrich Chemical Co. Potassium salicylate can be preparedby treating a hot, concentrated solution of salicylic acid with anequivalent amount of potassium hydroxide, preferably as a concentratedsolution, and then cooling to separate potassium salicylate.

[0107] Sodium dodecylsulfate is commercially available from AldrichChemical Co. Potassium dodecylsulfate can be prepared by recrystallizingthe sodium salt in the presence of an excess of potassium chloride.

[0108] Di(2-ethylhexyl)phosphoric acid is commercially available fromAldrich Chemical Co. Sodium di(2-ethylhexyl)phosphate, can be preparedby treating a toluene solution of the acid with an excess of sodiumhydroxide as an aqueous solution. A 2-phase system results, with thesodium salt in the toluene phase. Separation of the phases followed bydistillation of the toluene yields a residue that is sodiumdi(2-ethylhexyl)phosphate. The potassium salt is obtained analogously,except that a potassium hydroxide solution is used in the place of thesodium hydroxide solution.

[0109] 1-Hexadecylsulfonic acid sodium salt is commercially availablefrom Aldrich Chemical Co. Potassium 1-hexadecylsulfonate can be obtainedfrom the sodium salt by recrystallization in the presence of a smallexcess of potassium chloride.

[0110] Sodium salts of phosphatidic acids are commercially availablefrom Avanti Polar Lipids, Alabaster, Ala.

[0111] It should be recognized that the compositions, kits, and methodsof the present invention are not limited to the use of a single type offacilitating anion. If necessary or desirable, two or more differenttypes of facilitating anions can be used.

[0112] It should also be recognized that the bretylium cation and thefacilitating anion can be from the same compound or from differentcompounds. For example, the source of the bretylium cation and thesource of the facilitating anion may be a single compound comprising thebretylium cation and the facilitating anion, such as a pharmaceuticallyacceptable salt wherein the bretylium cation is paired with thefacilitating anion. Such compounds include, for example:

[0113] a) bretylium di(2-ethylhexyl)sulfosuccinate;

[0114] b) bretylium salicylate;

[0115] c) bretylium acetylsalicylate;

[0116] d) bretylium di(2-ethylhexyl)phosphate;

[0117] e) bretylium lauryl sulfate; and

[0118] f) bretylium hexadecylsulfonate.

[0119] Source of the β-Receptor Blocker

[0120] The compositions and kits of the present invention concerningbretylium may contain one or more pharmaceutically acceptable β-receptorblockers (preferably, a β-receptor blocker that does not antagonize thetherapeutic effect of the bretylium cation). It has been found inaccordance with this invention that a β-receptor blocker often producesa synergistic improvement in the therapeutic effect of the bretyliumcation. For example, a β-receptor blocker tends to (1) synergisticallyincrease the rate at which the bretylium cation affectsanti-fibrillatory action, and/or (2) synergistically enhance theanti-fibrillatory action of the bretylium cation.

[0121] Suitable β-receptor blockers generally include, but are notlimited to, propranolol (also known as “Inderal”), atenolol, esmolol,metoprolol, labetalol, talinolol, timolol, acebutolol,dichloroisoproterenol, pronethalol, sotalol, oxprenolol, alprenolol,practolol, nadolol, pindolol, penbutolol, and carvedilol. Preferably,the β-receptor blocker comprises propranolol, atenolol, esmolol,metoprolol, talinolol, timolol, or acebutolol. In a particularlypreferred embodiment, the β-receptor blocker comprises propranolol. Inanother particularly preferred embodiment, the β-receptor blockercomprises esmolol (particularly in instances where the composition isbeing administered via injection and/or the facilitating anion is laurylsulfate, sulfosuccinate, or salicylate). In yet a further particularlypreferred embodiment, the β-receptor blocker comprises metoprolol.

[0122] Propranolol is commercially available from, for example,Wyeth-Ayerst Laboratories, Philadelphia, Pa. Atenolol is commerciallyavailable from, for example, Zeneca Pharmaceuticals, Wilmington, Del.Esmolol is commercially available from, for example, Baxter HealthcareCorp., Deerfield, Ill. Metoprolol is commercially available from, forexample, Novartis, East Hanover, N.J. Labetalol is commerciallyavailable from, for example, Schering-Plough Pharmaceuticals, Madison,N.J. Acebutolol is commercially available from, for example,Wyeth-Ayerst Laboratories. Carvedilol is commercially available from,for example, SmithKline Beecham, Philadelphia, Pa. Sotalol iscommercially available from, for example, Berlex Laboratories, Inc.,Wayne, N.J. Nadolol is commercially available from, for example,Bristol-Myers Squibb Co., Stamford, Conn.

[0123] Source of the Neutralizing Agent

[0124] The compositions and kits of the present invention (particularlythose intended to be orally administered) may optionally contain one ormore neutralizing agents. The neutralizing agent may be anypharmaceutically acceptable material that increases the pH of thestomach when ingested, and that is chemically compatible with thebretylium cation and the facilitating anion selected. Preferably, theneutralizing agent is physiologically inert other than for pH adjustmentpurposes, and is not absorbed or only minimally absorbed from thegastrointestinal tract. Examples of particularly preferred neutralizingagents are those selected from the group consisting of pharmaceuticallyacceptable alkali metal carbonates (e.g., sodium bicarbonate orpotassium hydrogen carbonate); alkali metal citrates (e.g., sodiumcitrate); alkali metal phosphates (e.g., disodium phosphate); alkalimetal salts of carboxylic acids (e.g., alkali metal salts of aceticacid, tartaric acid or succinic acid); alkaline earth metal hydroxides(e.g., magnesium hydroxide); and mono-, di-, and polyamino-sugars (e.g.,methyl glucamine, i.e., meglumine). In one of the more preferredembodiments, the neutralizing agent comprises sodium bicarbonate, sodiumcitrate, or a combination thereof, which are each non-toxic and have alower equivalent weight than most other suitable neutralizing agents.For example, in a preferred embodiment, it has been found that acommercially available Alka Seltzer® tablet comprising sodiumbicarbonate, citric acid and aspirin can act as a sufficientneutralizing agent.

[0125] A neutralizing agent permits the use of a broader class offacilitating anions. More specifically, because the preferredfacilitating anions are conjugate bases of acids having a pK_(a) valuelower than or equal to the ambient pH of the stomach, a neutralizingagent can be used to temporarily increase the stomach pH in a subject toexpand the range of suitable facilitating anions. When a neutralizingagent is employed, the facilitating anion selected preferably is theconjugate base of an acid having a pK_(a) value at least about one unitless than the ambient pH as adjusted by the neutralizing agent, morepreferably the conjugate base of an acid having a pK_(a) value at leastabout 1.5 units less than the ambient pH as adjusted by the neutralizingagent, and still more preferably the conjugate base of an acid having apK_(a) value at least about 2 units less than the ambient pH as adjustedby the neutralizing agent.

[0126] Source of the Buffering Agent

[0127] The composition and kits of the present invention (particularlythose intended for oral administration, and even more particularly thosecontaining a neutralizing agent) may optionally contain one or morebuffering agents to prevent an excessive increase in the pH of theaqueous contents of the stomach. The buffering agent may comprise anypharmaceutically acceptable buffering agent. Suitable buffering agentsinclude, but are not limited to, pharmaceutically acceptable acids(e.g., citric acid). In a particularly preferred embodiment, thebuffering agent is a pharmaceutically acceptable acid having a pK_(a)value of at least about 1 unit (and more preferably at least about 2units) greater than the pK_(a) value of the conjugate acid of thefacilitating anion selected. Even more preferably, the buffering agentis an acid having a pK_(a) value of from about 4.5 to about 5.5.

[0128] Source of the Anti-Hypotensive Agent

[0129] The compositions and kits of the present invention may optionallycontain one or more pharmaceutically-acceptable anti-hypotensive agents,which reduce or eliminate orthostatic hypotension caused by thebretylium cation. The anti-hypotensive agent preferably operates toreduce or eliminate the orthostatic hypotension by blocking the uptakeof the bretylium cation into the sympathetic nerves. Suitableanti-hypotensive agents include, but are not limited to, tricyclicanti-depressant compounds selected from the group consisting ofprotriptyline, mazindol, amitriptyline, nortriptyline, desipramine, withprotriptyline being especially preferred. Protriptyline is commerciallyavailable from, for example, Sidmak Labs, Inc., East Hanover, N.J.

[0130] In a particularly preferred embodiment, the anti-hypotensiveagent(s), in addition to reducing or eliminating orthostatic hypotensioncaused by the bretylium cation, also enhance the therapeutic effect ofthe bretylium cation by, for example, raising the electrical ventricularfibrillation threshold. Anti-hypotensive agents, particularly tricyclicanti-depressant compounds discussed above, often synergize thetherapeutic effect of the bretylium cation, thereby lowering the dose ofthe bretylium cation needed, for example, to suppress ventriculartachyarrhythmias.

[0131] Epinephrine, a synthetic sympathomimetic adrenergic drug, mayalso be used to reverse orthostatic hypotension.

[0132] Utility of the Compositions and Kits of the Present Invention

[0133] The compositions and kits of the present invention are usefulfor, but not limited to, treating conditions (i.e., medical disorders orotherwise) which have conventionally been treated by administering thebretylium cation (particularly in the form of bretylium tosylateinjectable compositions). In general, the compositions and kits areuseful where it is desirable to accomplish one or more of the following:

[0134] 1. Prevent sudden cardiac death.

[0135] 2. Prevent and/or treat myocardial infarction.

[0136] 3. Prevent and/or treat congestive heart failure (particularly byinducing sympathetic blockade), such as by reducing oxidative metabolismin the heart by blocking norepinephrine release.

[0137] 4. Prevent and/or treat ventricular fibrillation (particularly byraising the ventricular fibrillation threshold).

[0138] 5. Prevent and/or treat ventricular arrhythmia in general.

[0139] 6. Prevent and/or treat ventricular tachycardia.

[0140] 7. Prevent and/or treat ventricular premature heartbeats.

[0141] 8. Prevent and/or treat atrioventricular dissociation.

[0142] 9. Prevent and/or treat multifocal ectopic beats.

[0143] 10. Prevent and/or treat premature ventricular extrasystoles.

[0144] 11. Prevent and/or treat bigeminal rhythm.

[0145] 12. Prevent and/or treat trigeminal rhythm.

[0146] 13. Prevent and/or treat angina pectoris (most notably bysympathetic blockade; optionally with the administration of bethanidinesulfate).

[0147] 14. Prevent and/or treat coronary insufficiency (most notably bysympathetic blockade).

[0148] 15. Prevent and/or treat sympathetically induced pain, such aswith causalgia.

[0149] 16. Restore and/or maintain normal sinus rhythm.

[0150] 17. Increase the effective ventricular refractory period.

[0151] 18. Increase the sinus automaticity transiently.

[0152] 19. Prolong the Purkinje action potential duration.

[0153] 20. Induce post-ganglionic sympathetic blockade, thereby reducingoxidative metabolism in the heart, reducing the heart rate, and reducingthe blood pressure.

[0154] 21. Block the sympathetic nervous system, typically by blockingthe release of norepinephrine at sympathetic nerve endings or ganglia,and/or by blocking β-receptors.

[0155] 22. Reduce vascular impedance, and, in particular, reducecoronary resistance.

[0156] 23. Increase the ventricular fibrillation threshold.

[0157] 24. Prolong the action potential duration of cardiac cells.

[0158] 25. Prevent the sympathetic reflex by blocking the same, whichoccurs when congestive heart failure increases central venous pressureor atrial pressure inducing coronary artery vasoconstriction. Activationof the sympathetic reflex causes reflex coronary constriction with adecrease in coronary blood flow that perpetuates congestive heartfailure in a vicious cycle by increasing myocardial ischemia, whichwould then further reduce contractile strength and pumping capacity ofthe myocardium, thereby further augmenting congestive heart failure.

[0159] 26. Prevent and/or treat the occurrence of shock in a patient,particularly a patient susceptible to or suffering from septic shock,hemorrhagic shock, cardiogenic shock and/or hypovolemic shock.

[0160] The pharmaceutical compositions and kits of the present inventionare particularly advantageous because they generally act in two separateways to treat the above conditions: (1) the compositions and kits of thepresent invention have an anti-fibrillatory effect (i.e., it is believedthat the compositions and kits of the present invention directly act onthe ionic currents in the myocardial heart cells to prevent and/or treatfibrillation) by blocking potassium outward current and modulatingcalcium current and (2) the compositions and kits of the presentinvention have a sympathetic nervous system blocking effect (i.e., it isbelieved that they block the release of the nerve transmitternorepinephrine from the sympathetic ganglia and nerve endings, therebyreducing or entirely eliminating the coronary artery constriction,platelet aggregation, and/or oxygen waste normally caused by the releaseof the nerve transmitter).

[0161] It also has been discovered in accordance with this inventionthat the compositions and kits of this invention (particularly thosecomprising a source of the salicylate anion, and most preferably thosecomprising an acetylsalicylate anion, less preferably those comprising asource of lauryl sulfate or di(2-ethylhexyl sulfosuccinate)) may be usedto prevent and/or treat atrial arrhythmia, most notably atrialfibrillation (as well as atrial tachycardia). Atrial fibrillation isreported to be probably the most common cardiac arrhythmia. Although itis often not a life-threatening arrhythmia, atrial fibrillation isbelieved to be associated with strokes caused by blood clots forming inareas of stagnant blood collected in the non-contracting atrium as aresult of the atrial fibrillation. Atrial fibrillation also isassociated with loss of the atrial-ventricular synchrony, and thereforecan result in an irregular heart rate and/or a hemodynamicallyinefficient cardiac performance. In addition, atrial fibrillation maycause, for example, palpitations of the heart, dyspnea (i.e., difficultyin breathing), fatigue, angina pectoris (i.e., pain in the region of theheart), dizziness, or even loss of consciousness. Thus, the use of thecompositions and kits of the present invention to prevent and/or treatatrial arrhythmia can ultimately offer several benefits by reducing oreliminating one or more of these conditions. And, the compositions andkits of the present invention may be used without causing the traumanormally associated with many conventionally used techniques forconverting atrial fibrillation to sinus rhythm (most notably, shockingthe chest wall or implantation of an atrial defibrillator).

[0162] It should be recognized that the compositions and kits of thisinvention may be used in conjunction with or as a replacement for otherantiarrhythmic agents, adrenergic neuronal blocking agents (e.g.,lidocaine), and/or therapeutic agents useful for the treatment ofcongestive heart failure (e.g., ACE inhibitors and/or digitalis).

[0163] It should further be recognized that these compositions and kitsare useful for human treatment, as well as veterinary treatment ofcompanion animals, exotic animals, and farm animals. More preferredrecipients include mammals, particularly humans, horses, dogs, and cats.

[0164] Dosages

[0165] A. Dosage of the Bretylium Cation

[0166] The pharmaceutical compositions and kits of the present inventionpreferably contain the bretylium cation in an amount sufficient toadminister from about 0.1 to about 3000 mg (more preferably from about20 to about 1600 mg, and still more preferably from about 40 to about1000 mg) of the bretylium cation. When the source of the bretyliumcation is bretylium tosylate, the pharmaceutical composition or kitpreferably contains from about 0.2 to about 5000 mg (more preferablyfrom about 40 to about 2500 mg, and still more preferably from about 80to about 2000 mg) of bretylium tosylate.

[0167] A daily dose of the pharmaceutical composition or kit preferablyadministers an amount of the bretylium cation sufficient to provide fromabout 0.001 to about 50 mg (more preferably from about 0.6 to about 18mg, and still more preferably from about 1 to about 18 mg) of thebretylium cation per kg of the recipient's body weight per day. When thesource of the bretylium cation is bretylium tosylate, a daily dose ofthe pharmaceutical composition or kit preferably administers from about0.002 to about 50 mg (more preferably from about 1 to about 30 mg, andstill more preferably from about 2 to about 30 mg) of bretylium tosylateper kg of the recipient's body weight per day.

[0168] It should be recognized that the preferred daily dose of thebretylium cation will depend on various factors. One such factor is thespecific condition being treated. For example, the preferred daily doseof the bretylium cation for an anti-infarction therapeutic effect isfrom about 1.0 to about 5.0 mg/kg body weight per day, while thepreferred daily dose for an anti-fibrillatory therapeutic effect is fromabout 0.5 to about 50.0 mg/kg body weight per day, typically from about0.5 to about 30 mg/kg body weight per day, and the preferred daily dosefor a sympathetic blockade therapeutic effect is from about 1.0 to about2.0 mg/kg body weight per day. Other factors affecting the preferreddaily dose include, for example, the age, weight, and sex of thesubject; the severity of the condition being treated; and the route andfrequency of administration. In many instances, the preferred dailybretylium cation dosage will be the same as the dosage employed ininjectable bretylium tosylate compositions known to those of ordinaryskill in the art for obtaining the desired effect.

[0169] The daily dose is preferably administered in the form of from 1to 4 unit doses (e.g., administration from once every 6 hours to onceper day), more preferably from 2 to 3 unit doses (this preference stemsfrom the fact that the elimination half-life of the bretylium cation isfrom about 10 to 12 hours). When administered orally, the daily dose maybe administered in the form of a unit dose of a composition comprisingthe bretylium cation or as part of a kit comprising a source of thebretylium cation. Unit dosage forms typically administer, for example, a10, 20, 25, 37.5, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, or 400mg dose of the bretylium cation for an average-size human (average-sizebeing about 75 kg). Where the bretylium cation is provided in the formof bretylium tosylate, dosage units are preferably capsules or tabletscontaining about 120, 240, or 360 mg of bretylium tosylate. The dosageunit form may be selected to accommodate the desired frequency ofadministration used to achieve the specified daily dosage. It should berecognized that the amount of the unit dosage and the dosage regimen fortreating a condition may vary widely and will depend on a variety offactors, including the age, weight, sex, and medical condition of thesubject; the severity of the condition; and the route and frequency ofadministration. For example, subjects with impaired renal function mayrequire a lesser amount of the bretylium cation relative to subjectswith normal renal function due to the higher clearance time needed toeliminate the bretylium cation, which is eliminated unchanged in theurine. Preferably, at least an equimolar amount (i.e., a 1:1 molarratio) or a small molar excess (i.e., from about a 1:1.1 to about a1:1.5 molar ratio) of the facilitating anion should be provided with thebretylium, and in a preferred embodiment, a 1:2 molar ratio is provided.Less preferably, a 1:0.5 molar ratio could be used, although there wouldbe less facilitating anion present to combine with the bretylium.

[0170] In a particularly preferred embodiment, only one unit dosage ofthe bretylium cation is administered per day. As has been discovered inaccordance with this invention, the benefits of the bretylium cation(e.g., increased ventricular fibrillation threshold) can generally beextended over time so that only 1 dose per day is preferred,particularly where the source of facilitating anion is, for example, asource of the salicylate anion, the lauryl sulfate anion, and/or thedi(2-ethylhexyl)sulfosuccinate anion. In one of the most preferredembodiments, the benefits of the bretylium cation are extended byadministering the bretylium cation with an acetylsalicylate anion (in anespecially preferred embodiment, the source of the bretylium cation(e.g., bretylium tosylate) is administered with an acetylsalicylateanion and a β-receptor blocker).

[0171] B. The Ratio of Facilitating Anion to Bretylium Cation

[0172] The pharmaceutical compositions and kits of the present inventionpreferably have a molar ratio of the facilitating anion to the bretyliumcation of at least about 1.0, more preferably at least about 1.1, stillmore preferably from about 1.1 to about 4, and still even morepreferably from about 1.1 to about 2. For example, when the facilitatinganion is an acetylsalicylate anion, it is preferred that the molar ratioof facilitating anion to bretylium cation is at least about 1.0, andmore preferably from about 1.1 to about 1.5. Lower molar ratios (i.e.,from about 0.5 to about 1.0) may also be used, but provide lessfacilitating anion.

[0173] C. Neutralizing Agent

[0174] As noted above, when the compositions or kits of the presentinvention are administered orally, the composition or kit preferablycomprises a neutralizing agent. The neutralizing agent preferably ispresent in an amount sufficient to increase the pH of the aqueouscontents of the stomach after ingestion to a value sufficient to preventthe absorption of a significant fraction of the facilitating anion asits conjugate acid into the gastrointestinal mucosa. More preferably,the amount of neutralizing agent is sufficient to temporarily increasethe pH of the aqueous contents of the stomach to at least about 2, morepreferably to at least about 3, and still more preferably to at leastabout 4. In a particularly preferred embodiment, the pH increases to atleast about 2 within less than about 1 minute, and remains greater thanabout 2 for at least about 15 minutes after administration of theneutralizing agent. Although an amount of neutralizing agent sufficientto increase the pH to a value greater than about 7 may be used, theamount preferably does not increase the pH to a value greater than about7. For most neutralizing agents, an amount of up to about 50 mmole(preferably from about 0.05 to about 50 mmole) is sufficient to achievethe desired pH increase in an average-size human. For example, whenusing sodium bicarbonate as the neutralizing agent in an average-sizehuman, the sodium bicarbonate preferably is administered in an amount offrom about 0.1 to about 4200 mg, more preferably from about 5 to about4200 mg, still more preferably from about 10 to about 4200 mg, and stilleven more preferably from about 1000 to about 4200 mg.

[0175] It should be recognized that the facilitating anion also mayfunction to increase the pH of the stomach when the facilitating anionis converted into its corresponding conjugate acid. Accordingly, theamount of neutralizing agent required may generally be reduced byincreasing the amount of the facilitating anion in the composition. Insome embodiments, the preference for a separate neutralizing agent maybe entirely eliminated by selection of an appropriate amount of asuitable facilitating anion.

[0176] In one embodiment, it is preferred to use sodium bicarbonate as aneutralizing agent in combination with citric acid as a buffering agentas described below and as found commercially, for example, in an AlkaSeltzer® tablet. In such an embodiment, the molar ratio of sodiumbicarbonate to citric acid is preferably between about 3:1 to about 5:1,with a 4:1 molar ratio most preferred. Thus, a preferred composition ofthe present invention including from about 1000 mg to about 2000 mg(e.g., about 1250 mg, 1500 mg or 1700 mg) of sodium bicarbonate willcontain from about 600 mg to about 1200 mg (e.g., about 750 mg, 900 mgor about 1000 mg) of sodium citrate.

[0177] D. Buffering Agents

[0178] As noted above, the compositions and kits intended to beadministered orally preferably comprise a buffering agent, particularlywhere a neutralizing agent is also included in the composition or kit.When a buffering agent is used in combination with a neutralizing agent,the molar ratio of buffering agent to neutralizing agent may varywidely. Preferably, the molar ratio of buffering agent to neutralizingagent is from about 0.25 to about 1.5, and more preferably about 1.Typically, the amount of buffering agent should be sufficient to bufferthe pH of the stomach between about 2 and 7 upon administration of theneutralizing agent.

[0179] In a particularly preferred embodiment as described above usingsodium bicarbonate as a neutralizing agent in combination with citricacid as a buffering agent, the molar ratio of sodium bicarbonateneutralizing agent to citric acid buffering agent is preferably about4:1. Such formulations typically include from about 1000 to about 2000mg (e.g., about 1250 mg, 1500 mg or 1700 mg) of sodium bicarbonate willcontain from about 600 mg to about 1200 mg (e.g., about 750 mg, 900 mgor about 1000 mg) with about 1700 mg sodium bicarbonate and about 1000mg citric acid comprising a preferred composition.

[0180] E. Anti-Hypotensive Agent

[0181] When the composition or kit comprises an anti-hypotensive agent(e.g., a tricyclic anti-depressant compound selected from the groupconsisting of protriptyline, mazindol, amitriptyline, nortriptyline, anddesipramine), the anti-hypotensive agent is preferably administered as asubtherapeutic dose relative to conventional dosages known to those ofordinary skill in the art. Such subtherapeutic doses of theanti-hypotensive agent in general are preferably from about 0.2 to 30mg/day (in divided doses) for an average-size human. This preferreddosage, however, varies with the anti-hypotensive agent selected. Forexample, when administered to an average-size human, it is preferred touse from about 2.0 to about 20 mg/dose for protriptyline for anaverage-size human, from about 0.2 to about 10 mg/dose for mazindol foran average-size human, from about 3.0 to about 30 mg/dose foramitriptyline for an average-size human, from about 2.0 to about 20mg/dose for nortriptyline for an average-size human, and from about 2.0to about 20 mg/dose for desipramine for an average-size human.

[0182] F. β-Receptor Blocker

[0183] When the composition or kit comprises a 1-receptor blocker (e.g.,propranolol, atenolol, esmolol, metoprolol, labetalol, talinolol,timolol, carvedilol, or acebutolol), the β-receptor blocker ispreferably administered as a subtherapeutic dose relative toconventional β-blocking dosages known to those of ordinary skill in theart. Such subtherapeutic doses of the β-receptor blocker typically varywith the compound selected. For example, the following dosages arepreferred for the following compounds: from about 0.05 to about 0.2 mgof propranolol per kg body weight for an average-size human; from about0.25 to about 0.1 mg of atenolol per kg body weight for an average-sizehuman; from about 20 to about 300 μg of esmolol per kg body weight foran average-size human; from about 0.035 to about 0.1 mg of metoprololper kg body weight for an average-size human; from about 100 to about350 mg of labetalal per kg body weight for an average-size human; fromabout 350 to about 500 mg of talinolol per kg body weight for anaverage-size human; from about 300 to about 750 mg of timolol per kgbody weight for an average-size human; and form about 50 to about 100 mgof acebutolol per kg body weight for an average-size human.

[0184] Methods of Use

[0185] As discussed above, the present invention is directed topreventing and treating cardiovascular conditions. The method comprisesadministering (orally or otherwise) a therapeutically-effective amountof one or more of the compositions or kits described above to a subjecthaving or susceptible to such a condition.

[0186] Initial treatment of a patient suffering from a medical conditionwhere treatment with the bretylium cation is appropriate can begin withthe dosages discussed above. In many instances, the treatment iscontinued as necessary over a period of several weeks to several monthsor years until the condition has been controlled or eliminated. Patientsundergoing treatment with the compositions or kits disclosed herein canbe routinely monitored by any of the methods well known in the art todetermine the effectiveness of therapy (e.g., by monitoring theprolongation of the QT_(c) interval in the electrocardiogram, etc.).Continuous analysis of such data permits modification of the treatmentregimen during therapy so that optimal effective amounts of thecompositions and kits of this invention may be administered at any pointin time, and so that the duration of treatment can be determined aswell. In this way, the treatment regimen and dosing schedule can berationally modified over the course of therapy so that the lowest amountof the bretylium cation exhibiting satisfactory effectiveness isadministered, and so that administration is continued only so long as isnecessary to successfully prevent or treat the condition.

[0187] In accordance with the present invention, it has been discoveredthat the amount of the bretylium cation absorbed and/or the rate ofabsorption of the bretylium cation from the gastrointestinal tract(particularly the intestine) into the blood (i.e., the blood plasma orotherwise) and from the blood into the target cells can generally beimproved by administering the bretylium cation (in a pharmaceuticallyacceptable source of the bretylium cation such as bretylium tosylate) toa subject, along with at least one source of lipophilic or weaklyhydrophilic anion (i.e., a facilitating anion), and, optionally: (i) oneor more neutralizing agents (e.g., sodium bicarbonate or sodium citrate)capable of temporarily increasing the pH of the aqueous contents in thestomach, (ii) one or more anti-hypotensive agents (e.g., protriptyline),(iii) one or more buffering agents (e.g., citric acid), and/or (iv) oneor more β-receptor blockers (e.g., propranolol, esmolol, and/ormetoprolol). This, in turn, generally provides improved bretylium cationconcentrations in the blood (and, particularly, in the myocardium) andconsequent improved bretylium cation AUC (area under the curve) valuesfor at least about 30 minutes (more preferably at least about 2 hours,even more preferably at least about 6 hours, still even more preferablyat least about 12 hours, and most preferably at least about 24 hours)following oral administration relative to the conventionally-tried oralcompositions (particularly unformulated bretylium tosylate), andultimately provides an improved efficacy of the bretylium cationadministered to a subject in need thereof.

[0188] Biological membranes are lipid in character, as are nerve fibers.The bretylium ions must reach the nerve sites in order to be effective,i.e., they must pass from the blood, across the nerve blood barrier tothe nerve fibers. If ingested orally, the bretylium ions must passthrough the lipid mucosa of the intestine to reach the bloodstream, andfrom there, be distributed to the nerve fibers.

[0189] Several methods can be used to transfer the bretylium. Inaccordance with the preferred method, bretylium bromide is formulatedwith a pharmaceutically acceptable alkali metal or alkaline earth saltof a much less hydrophilic anion than bromide. The salt is then placedin a preparation that allows for oral ingestion. Upon oral ingestion,the salts dissolve in the stomach and the facilitating anion of theinvention allows for greater uptake in the small intestine.

[0190] Alternatively, it is contemplated that salts of the bretyliumcation and a non-facilitating anion could be ingested along with a saltof a non-quaternary ammonium cation (e.g., sodium, potassium, calcium ormagnesium) and a facilitating anion. These salts could be combinedtogether in a composition or alternatively be made available in a kit.The bretylium cation and the facilitating anion associate in the stomachupon mixing without absorption in the stomach to allow uptake in thesmall intestine.

[0191] It is further contemplated that any of the above methods(compounds or kits) could include the use of neutralizing agents,buffering agents, anti-hypotensive agents and/or β-receptor blockers orbethanidine sulfate. Such reagents could be incorporated into thecompound or added into the kit. Use of neutralizing agents and bufferswould increase the stomach pH to from about 2 to 7 to allow furthereduptake. Use of anti-hypotensive agents would tend to counteract the sideeffects of the bretylium compounds (which tend to cause orthostatichypotension). Use of β-receptor blockers or bethanidine sulfate withbretylium enhances the effects of the bretylium on the patient in asynergistic effect.

[0192] For example, in accordance with the present invention, it hasbeen discovered that the use of a bretylium cation with anacetylsalicylate anion (i.e., acetylsalicylic acid or an alkali metalsalt thereof) and a β-receptor blocker (e.g., propranolol, esmolol,metoprolol, etc.) can significantly increase the electrical ventricularfibrillation threshold (VFT) in a subject (as measured by application ofan electrical current, for example, as described in Example 15 below).Specifically, it has been found that upon orally administering acomposition or kit of the present invention comprising a bretyliumcation, an acetylsalicylate anion and a β-receptor blocker to a subject,the electrical ventricular fibrillation threshold measured in thesubject about five minutes after administration of the composition orthe components of the kit is at least about 25% higher (e.g., about 35%,50%, 60%, 75%, 90% or 100% higher) than the electrical ventricularfibrillation threshold measured in the subject prior to theadministration of the pharmaceutical composition or the components ofthe pharmaceutical kit. Further, the electrical ventricular fibrillationthreshold measured in the subject about 30 minutes after theadministration of a pharmaceutical composition or the components of apharmaceutical kit comprising a bretylium cation, an acetylsalicylateanion and a β-receptor blocker is at least about two times higher (e.g.,about three, four, five or six times higher) than the electricalventricular fibrillation threshold measured in the subject beforeadministration of the pharmaceutical composition or the components ofthe pharmaceutical kit.

[0193] It should also be understood that the invention contemplates theadministration of the bretylium cations and the facilitating anionsthrough compositions which contain mixtures of salts, i.e., a salt ofthe bretylium cation and a non-facilitating anion mixed with a salt of anon-quaternary ammonium cation and a facilitating anion. Such acomposition could be ingested and allow the ions of interest to combinewithin the stomach and small intestine. Such mixtures would optionallyinclude the use of other components such as neutralizing agents,buffering agents, anti-hypotensive agents and/or β-receptor blockersand/or bethanidine sulfate.

[0194] Suitable facilitating anions have aqueous to organic partitioncoefficients substantially larger than that of chloride ion or bromideion. Examples include alkyl sulfates, alkyl sulfonates, monoalkyl anddialkyl phosphates, o-acyl salicylates, C-alkylsalicylates, andsalicylate ion itself. The aqueous to organic partition coefficientsmeasure the distribution ratio of the bretylium cation between anoctanol-rich liquid phase and the aqueous-rich phase.

[0195] To measure the partition coefficient for a facilitating anion inthe presence of a bretylium compound, an acidified aqueous solution ofthe bretylium compound with a non-facilitating anion (e.g., tosylate,bromide or chloride) is first prepared. Sodium bicarbonate and a saltcomprising the facilitating anion to be tested are then added to theaqueous solution. The salt comprising the facilitating anion should beadded in an amount sufficient to provide about a 1:1 molar ratio of thefacilitating anion to the bretylium cation. The sodium bicarbonate isprovided in an amount sufficient to produce a preselected pH value. Anequal volume of n-octanol is then added to this solution. The solutionis shaken. The mixture is centrifuged to separate an octanol-rich layerand an aqueous-rich layer, and the distribution ratio of the bretyliumcation between the octanol-rich phase and the aqueous-rich phase (thatis, the partition coefficient) may be measured. This analytical approachis believed to provide a suitable model for evaluating thebioavailability of the bretylium cation when utilized with afacilitating anion.

[0196] A. Order of Administration of the Bretylium Cation, theFacilitating Anion or β-Receptor Blocker, and Other Optional Ingredientsof a Kit

[0197] As noted above, a kit may be used in accordance with thisinvention, wherein the therapeutic ingredients to be administered arecontained in at least two separate, discrete sources. To illustrate, thesource of the bretylium cation may be separate and discrete from thesource of the facilitating anion and/or the source of the β-receptorblocker. Or, to illustrate further, the source of the bretylium cationmay also contain the facilitating anion, while the neutralizing agent iscontained in a separate, discrete source. Or to illustrate even further,the kits of the present invention may comprise two separate, discretesources of ingredients which each contain a bretylium cation and afacilitating anion. Regardless, the use of a kit provides the advantageof being able to administer two or more different ingredientsindependently of each other. This, in turn, permits, for example, moreeffective adjustment in the amount of the facilitating anion, β-receptorblocker, neutralizing agent, buffering agent, and/or anti-hypotensiveagent administered relative to the amount of the bretylium cationadministered.

[0198] Typically, when a kit is used, it is preferred that thefacilitating anion(s) and/or β-receptor blocker(s) (as well as anyneutralizing agent, buffering agent, and/or anti-hypotensive agent) beadministered jointly or within about 30 minutes before or after (andmore preferably within about 15 minutes before or after) the bretyliumcation is administered. An ingredient administered jointly with thebretylium cation may be administered as a component of a bretyliumcation source (i.e., where the bretylium cation source is a compositioncontaining the cation and the additional ingredient). Alternatively, theadditional ingredient may be administered as a component of a sourceseparate and distinct from the bretylium cation source (i.e., where thesource of the additional ingredient is administered simultaneously withthe cation source). Or, as another alternative, the source containingthe additional ingredient may be combined with the bretylium cationsource before the administration of the cation source, and therebyadministered as a composition containing the bretylium cation and theadditional ingredient.

[0199] In a particularly preferred embodiment, a kit is used whichcontains a source comprising a unit dosage of the bretylium cation and aseparate source comprising a unit dosage of a facilitating anion (e.g.,a kit containing a tablet comprising sodium acetylsalicylate oracetylsalicylic acid and a tablet comprising bretylium tosylate). Thekit may also contain one or more other ingredients (e.g., a neutralizingagent, a buffering agent, a antihypotensive agent, and/or a preceptorblocker which may be a component of the source of the bretylium cation,a component of the source of the facilitating anion, and/or a componentof a source separate from the sources of the bretylium cation andfacilitating anion.

[0200] In yet another particularly preferred embodiment, a sourcecontaining a unit dosage of a neutralizing agent (and, optionally, aunit dosage of a buffering agent) is initially administered. This isthen followed by the administration of a source(s) containing thebretylium cation and a facilitating anion.

[0201] In still another particularly preferred embodiment,administration of a source(s) of the bretylium cation and a facilitatinganion is followed (preferably immediately) by the administration of asource(s) containing a unit dosage of an anti-hypotensive agent and/or aβ-receptor blocker. Optionally, administration of the anti-hypotensiveagent may be delayed until the patient is to be ambulated.

[0202] B. Injectable Compositions

[0203] As noted above, many of the compositions and kits of the presentinvention may be administered parenterally. In one particularlypreferred embodiment of this invention, an injectable composition isused which comprises the bretylium cation and a facilitating anion(e.g., a salicylate anion or an acetylsalicylate anion). Such acomposition is particularly useful for the emergency treatment of, forexample, ventricular fibrillation or myocardial infarction.

[0204] In a particularly preferred embodiment, the injectablecomposition comprises (1) the bretylium cation, (2) a facilitatinganion, (3) a β-receptor blocker such as propranolol, and (4) a tricyclicantidepressant to prevent sympathetic blockade and a material decreasein blood pressure. Suitable tricyclic antidepressants are discussedabove in detail.

[0205] In another particularly preferred embodiment, the injectablecomposition comprises (1) the bretylium cation, (2) a facilitatinganion, and (3) a β-receptor blocker. Here, the facilitating anion ispreferably a salicylate or acetylsalicylate anion. In one of the mostpreferred embodiments, the injectable composition comprises: (1) thebretylium cation (preferably in the form of bretylium tosylate), (2)acetylsalicylic acid or an alkali metal salt of acetylsalicylic acid,and (3) a β-receptor blocker. In all these embodiments, the morepreferred β-receptor blockers are esmolol, metoprolol, and propranolol,with metoprolol and propranolol being the most preferred.

[0206] Other Quaternary Ammonium Cations

[0207] The pharmaceutical compositions and kits of the present inventionalso are useful for the oral administration of other nonpeptide cationictherapeutic agents, particularly therapeutic agents comprisingquaternary ammonium cations, in accordance with the compositions andkits discussed above. These pharmaceutical compositions and kits can beprepared as set forth in this application by replacing the bretyliumcation with a comparable molar fraction of a cation of the desiredcationic therapeutic agent, such as propyromazine.

[0208] Forms of Pharmaceutical Compositions for the Quaternary AmmoniumCation and Facilitating Anion(s)

[0209] The pharmaceutical compositions of the present inventiondescribed above may also comprise one or more non-toxic,pharmaceutically-acceptable carriers, excipients, and/or adjuvants(collectively referred to herein as “carrier materials”). Thepharmaceutical compositions of the present invention may be adapted foradministration by any suitable route by selection of appropriate carriermaterials and a dosage of the quaternary ammonium cation effective forthe intended treatment.

[0210] The techniques used to prepare the pharmaceutical compositions ofthis invention vary widely, and include the well known techniques ofpharmacy for admixing the components of a medicine composition. Ingeneral, the compositions are prepared by uniformly and intimatelyadmixing the active compounds (in the form of, for example, powders)with or without a liquid or finely divided solid carrier, or both, andthen, if necessary, encapsulating or shaping the product. For example, atablet may be prepared by compressing or molding a powder or granules ofthe compound, optionally with one or more accessory ingredients.Compressed tablets may be prepared by compressing, in a suitablemachine, the compound in a free-flowing form, such as a powder orgranules optionally mixed with a binding agent, lubricant, inertdiluent, and/or surface active/dispersing agent(s). Molded tablets canbe made by molding, in a suitable machine, the powdered compoundmoistened with an inert liquid diluent.

[0211] In a particularly preferred embodiment, the composition isintended to be administered orally. In this instance, the carriermaterial(s) may be solid and/or liquid. Preferably, such a compositionis formulated as a unit-dose composition, i.e., the pharmaceuticalcomposition contains a desired specific amount of the quaternaryammonium cation and the facilitating anion, and is in the form of, forexample, a tablet (with or without a coating), a hard or soft capsule, alozenge, a cachet, a dispensable powder, granules, a suspension, anelixir, a liquid, or any other form reasonably adapted for oraladministration. Liquid dosage forms for oral administration include, forexample, pharmaceutically acceptable emulsions, solutions, suspensions,syrups, aerosols and elixirs containing inert diluents commonly used inthe art, such as water or gas. Such compositions may also comprise, forexample, wetting agents; emulsifying and suspending agents; andsweetening, flavoring, and perfuming agents. An excellent source whichdiscusses in detail methods for preparing oral compositions (both solidand liquid) is Pharmaceutical Dosage Forms: Tablets, Second Edition,Revised and Expanded, Vol. 1-3 (ed. by Lieberman, H. A., Lachman, L., &Schwartz, J. B., Marcel Dekker, Inc., 270 Madison Ave, New York, N.Y.1989) and Pharmaceutical Dosage Forms: Disperse Systems, Vol. 1-2 (ed.by Lieberman, H. A., Rieger, M. M., & Banker, G. S., Marcel Dekker,Inc., 270 Madison Ave, New York, N.Y. 1989).

[0212] The following discussion describes some of the more typical typesof carrier materials that may be used in accordance with this invention.It should be recognized, however, that other carrier materials (such ascolorants, flavors, sweeteners, and preservatives) are known in thepharmaceutical art, and may be used in the preparation of thepharmaceutical compositions of the present invention.

[0213] A. Diluents

[0214] The pharmaceutical compositions of the present invention mayoptionally comprise one or more pharmaceutically-acceptable diluents.Examples of suitable diluents include, either individually or incombination: lactose USP; lactose USP, anhydrous; lactose USP, spraydried; starch USP; directly compressible starch; mannitol USP; sorbitol;dextrose monohydrate; microcrystalline cellulose NF; dibasic calciumphosphate dihydrate NF; sucrose-based diluents; confectioner's sugar;monobasic calcium sulfate monohydrate; calcium sulfate dihydrate NF;calcium lactate trihydrate granular NF; dextrates, NF (e.g., Emdex);Celutab; dextrose (e.g., Cerelose); inositol; hydrolyzed cereal solidssuch as the Maltrons and Mor-Rex; amylose; Rexcel; powdered cellulose(e.g., Elcema); calcium carbonate; glycine; bentonite;polyvinylpyrrolidone; and the like.

[0215] B. Disintegrants

[0216] The pharmaceutical compositions of the present invention mayoptionally comprise one or more pharmaceutically-acceptabledisintegrants, particularly for tablet formulations. Examples ofsuitable disintegrants include, either individually or in combination:starches; sodium starch glycolate; clays (such as Veegum HV); cellulosesand various modifications of celluloses (such as purified cellulose,methylcellulose and sodium carboxymethylcellulose, andcarboxymethylcellulose); alginates; pregelatinized corn starches (suchas National 1551 and National 1550); Crospovidone, USP NF; gums (such asagar, guar, locust bean, Karaya, pectin, tragacanth); and the like.

[0217] C. Binding Agents and Adhesives

[0218] The pharmaceutical compositions of the present invention mayoptionally contain one or more binding agents or adhesives, particularlyfor tablet formulations. Such a binding agent or adhesive preferablyimparts sufficient cohesion to the powders to allow for normalprocessing, such as sizing, lubrication, compression and packaging,while also allowing the tablet to disintegrate and the composition todissolve upon ingestion. Examples of suitable binding agents andadhesives include, either individually or in combination: acacia;tragacanth; sucrose; gelatin; glucose; starch; cellulose materials(e.g., methylcellulose and sodium carboxymethylcellulose (e.g.,Tylose)); alginic acid and salts of alginic acid; magnesium aluminumsilicate; polyethylene glycol; guar gum; polysaccharide acids;bentonites; polyvinylpyrrolidone; polymethacrylates;hydroxypropylmethylcellulose (HPMC); hydroxypropylcellulose (Klucel);ethylcellulose (Ethocel); pregelatinized starch (e.g., National 1511 andStarch 1500); and the like.

[0219] D. Wetting Agents

[0220] The pharmaceutical compositions of the present invention mayoptionally contain one or more pharmaceutically-acceptable wettingagents. Such wetting agents preferably maintain the bretylium cation,and, where desired, other ingredients of the composition in suspension,and improve the relative bioavailability of the pharmaceuticalcomposition. Examples of suitable wetting agents include, eitherindividually or in combination: oleic acid; glyceryl monostearate;sorbitan mono-oleate; sorbitan monolaurate; triethanolamine oleate;polyoxyethylene sorbitan mono-oleate; polyoxyethylene sorbitanmonolaurate; sodium oleate; sodium lauryl sulfate; and the like.

[0221] E. Lubricants

[0222] The pharmaceutical compositions of the present invention mayoptionally contain one or more pharmaceutically-acceptable lubricants.The lubricant preferably (1) imparts a surface to the composition (e.g.,in the form of a tablet or capsule) that allows simple removal of thecomposition from a mold, and/or (2) increases the ability of thecomponents of the composition to be mixed evenly and readily. Examplesof suitable lubricants include, either individually or in combination:glyceryl behapate (Compritol 888); stearates (magnesium, calcium,sodium); stearic acid; hydrogenated vegetable oils (e.g., Sterotex);talc; waxes; Stearowet; boric acid; sodium benzoate and sodium acetate;sodium fumarate; sodium chloride; DL-Leucine; polyethylene glycols(e.g., Carbowax 4000 and Carbowax 6000); sodium oleate; sodium benzoate;sodium acetate; sodium lauryl sulfate; magnesium lauryl sulfate; and thelike.

[0223] F. Anti-Adherent Agents and Glidants

[0224] The pharmaceutical compositions of the present inventionoptionally may comprise one or more anti-adherent agents and/orglidants. Examples of suitable anti-adherents and glidants include,either individually or in combination: talc, corn starch, Cab-O-Sil,Syloid, DL-Leucine, sodium lauryl sulfate, metallic stearates, and thelike.

[0225] G. Enteric Coatings

[0226] In a particularly preferred embodiment, the pharmaceuticalcomposition is in an enteric form, i.e., the pharmaceutical compositioncomprises a coating which is resistant to degradation in the stomach,but will decompose in the intestinal tract. In such an instance, thepharmaceutical composition is typically in the form of a tablet orcapsule. Enteric coating materials are well-known in the art. Forexample:

[0227] 1. In U.S. Pat. No. 4,849,227, Cho describes enteric coatingscontaining: hydroxypropyl methylcellulose phthalate, polyethyleneglycol-6000, and/or shellac.

[0228] 2. In U.S. Pat. No. 5,814,336, Kelm et al. describe polymerenteric coatings having a thickness of at least about 250 μm, andcontaining a polyanionic polymer that is insoluble in water and aqueoussolutions having a pH of less than about 5 to about 6.3. Examples ofcoating materials that Kelm et al. report to be suitable are celluloseacetate phthalate, cellulose acetate trimelliate, hydroxypropylmethylcellulose phthalate, hydroxypropyl methyl cellulose acetatesuccinate, polyvinyl acetate phthalate, poly(methacrylic acid, methylmethacrylate) 1:1, poly(methacrylic acid, ethyl acrylate) 1:1, andcompatible mixtures thereof.

[0229] 3. In U.S. Pat. No. 5,914,132, Kelm et al. disclose amultilayered polymer enteric coating to prevent the release of an activeingredient until near the junction between the small intestine and thecolon (or while in the colon). This multilayered coating has (1) anouter layer which has a thickness of from about 20 to about 50 μm, andbegins to dissolve at a pH of between about 6.8 and about 7.2; and (2)an inner layer which has a thickness of roughly from about 90 to about300 μm, and begins to dissolve at a pH of between about 5 and 6.3.Examples of coating materials that Kelm et al. report to be suitable forthe outer coating are poly(methacrylic acid, methyl methacrylate) 1:2,and mixtures of poly(methacrylic acid, methyl methacrylate) 1:1 andpoly(methacrylic acid, methyl methacrylate) 1:2 in a ratio of about 1:10to about 1:2. Examples of coating materials that Kelm et al. report tobe suitable for the inner coating are the same as those described asbeing suitable coatings in U.S. Pat. No. 5,814,336.

[0230] 4. In U.S. Pat. No. 5,733,575, Mehra et al. describe entericcoatings made of titanized polyvinyl acetate phthalate, polyvinylacetate phthalate which has been jet milled, hydroxypropylmethylcellulose phthalate, hydroxypropyl methylcellulose acetatesuccinate, or cellulose acetate phthalate.

[0231] See also, e.g., Shaffer et al., U.S. Pat. No. 4,147,768; Maruyamaet al., U.S. Pat. No. 5,750,148; Kukubo et al., U.S. Pat. No. 5,776,501;and Gardner et al., U.S. Pat. No. 5,980,951.

[0232] H. Injectable Compositions

[0233] The compositions of this invention are generally not limited tobeing used orally. In general, they also may be administered byinjection (intravenous, intramuscular, subcutaneous, or jet) if desired.Such injectable compositions may employ, for example, saline, dextrose,or water as a suitable carrier material. The pH of the composition maybe adjusted, if necessary, with a suitable acid, base, or buffer.Suitable bulking, dispersing, wetting, or suspending agents (e.g.,mannitol and polyethylene glycol (such as PEG 400)), may also beincluded in the composition. A suitable parenteral composition can alsoinclude eplerenone in injection vials. Aqueous solutions can be added todissolve the composition before injection. The compositions of thisinvention may also be contained in pre-filled syringes for emergencyuse.

[0234] An excellent source which discusses in detail methods forpreparing injectable compositions is Pharmaceutical Dosage Forms:Parenteral Medications, Vol. 1-2 (ed. by Avis, K. E., Lachman, L., &Lieberman, H. A., Marcel Dekker, Inc., 270 Madison Ave, New York, N.Y.1989).

[0235] I. Resuscitation Solutions

[0236] In an especially preferred embodiment, the compositions of thepresent invention are in the form of a resuscitation solution suitablefor administration to a patient suffering from atrial fibrillation orsudden cardiac arrest. Generally, such resuscitation solutioncompositions comprise a salt of bretylium, acetylsalicylic acid or analkali metal salt of acetylsalicylic acid, a β-receptor blocker and aneutralizing agent dissolved in an aqueous carrier such as an aqueoussolution of 5% glucose. For example, in a preferred composition, theresuscitation solution comprises bretylium tosylate, acetylsalicylicacid, propranolol and methyl glucamine (i.e., meglumine). In analternative preferred composition, the resuscitation solution comprisesbretylium tosylate, acetylsalicylic acid, metoprolol and methylglucamine. Optionally, the resuscitation solution compositions mayfurther comprise an anti-hypotensive agent such as epinephrine ormethomamine and/or compounds such as V74389G or V74006F, which mayprotect the brain by preventing lipid peroxidation during atrialfibrillation.

[0237] Preferred dosages for the resuscitation solution compositionscomprise from about 5 mg/kg to about 20 mg/kg bretylium ion (preferablyabout 15 mg/kg bretylium ion); from about 2.5 mg/kg to about 10 mg/kgacetylsalicylic acid (preferably about 7.5 mg/kg acetylsalicylic acid);and from about 0.25 mg/kg to about 2 mg/kg of a β-receptor blocker(preferably 1 mg/kg for propranol, 0.5 mg/kg for metoprolol and 0.5ug/kg for esmolol). Optionally, the dosages may further comprise fromabout 0.2 meq/kg to about 0.4 meq/kg (preferably 0.3 meq/kg) of an aminosugar neutralizing agents such as methyl glucamine, i.e. meglumine; fromabout 0.19 ug/kg to about 1 mg/kg, preferably 0.3 mg/kg of ananti-hypotensive agent such as epinephrine; from about 0.1 mg/kg toabout 0.3 mg/kg, preferably 0.2 mg/kg of V74389G; and/or from about 0.1mg/kg to about 0.3 mg/kg, preferably 0.3 mg/kg of V74389G. For example,in a preferred resuscitation solution, the composition of the presentinvention comprises bretylium tosylate (15 mg/kg) and acetylsalicylicacid (7.5 mg/kg) with propranolol (1 mg/kg) or metoprolol (0.5 mg/kg)and/or epinephrine (0.2 mg/kg), V74309G (0.3 mg/kg) or V74006F (0.3mg/kg).

[0238] The resuscitation solution compositions described above areuseful in treating patients suffering from atrial fibrillation. Forexample, it has been found that administering such a resuscitationsolution either alone or in combination with conventionally usedthrombolitic therapies for converting atrial fibrillation to sinusrhythm (most notably, shocking the chest wall or implantation of anatrial defibrillator) to a patient suffering from atrial fibrillationcan help return a patient to normal sinus rhythm. Preferably, it isdesired to administer the resuscitation solution to a patientimmediately upon suffering atrial fibrillation. However, when theresuscitation solution is administered to a patient in co-ordinationwith another thrombolitic thereapy or an external defibrillatory shock,it is preferred to administer the resuscitation solution composition tothe patient prior to the administration of the thrombolitic therapy orbefore a first defibrillatory shock. Alternatively, the resuscitationsolution may be administered immediately following a firstdefibrillatory shock. When used with an external shock, theresuscitation solution may be administered at any time before or afterthe defibrillatory shock, including from about five minutes (e.g., 5, 4,3, 2 or 1 minute) to about 30 seconds before a defibrillatory shock toabout five minutes (e.g., 5, 4, 3, 2, 1 minute) to about 30 seconds orimmediately after shocking the chest wall. Further, when used incombination with an external defibrillatory shock, it has been foundthat administering the resuscitation solution compositions (eitherorally or parenterally) to a patient suffering from atrial fibrillationprior to shocking the chest wall can reduce and/or prevent aortic traumanormally associated external defibrillation.

[0239] PREPARATION OF BRETYLIUM SALTS WITH HYDROPHOBIC OR WEAKLYHYDROPHILIC ANIONS

[0240] Further in accordance with the invention, an advantageous processis provided for producing a salt of a bretylium cation and a relativelyhydrophobic anion, i.e., more hydrophobic than a halide ion or atosylate anion. In this process, an aqueous solution of a mineral acidsalt of the bretylium cation is mixed with a source of alkali metal oralkaline earth metal salt of said anion. The resulting mixture is thencontacted with a substantially water-immiscible organic solvent, therebytransferring the relatively hydrophobic salt of the bretylium cation andthe more hydrophobic anion to the solvent phase and producing an organicextract comprising the transferred salt. An alkaline or alkaline earthsalt of the mineral acid remains in the raffinate phase.

[0241] Preparation of Bretylium Halide

[0242] A bretylium halide salt, e.g.,2-bromobenzylethyl-dimethylammonium bromide, may conveniently beprepared by reaction of 2-bromobenzyl halide with ethyldimethylamine inthe presence of water. In this process, 2-bromobenzylbromide is mixedwith water, preferably in a ratio of between about 0.1 and 2 moles, morepreferably between about 0.3 and about 1.6 moles, most preferablybetween about 0.9 and about 1.1 moles of 2-benzylbromide per liter ofwater. A two phase liquid mixture is obtained. Ethyldimethylamine isadded to the mixture, preferably in small incremental portions, andpreferably up to a total of between about 2 and about 6 molesethyldimethylamine per mole of 2-bromobenylbromide, more preferably in aratio of 3 to 5 moles, most preferably in a range of 3.5 to 4.5 moles,per mole 2-bromobenzylbromide. Ethyldimethylamine serves both asreactant and buffer for the reaction. To provide further control of thepH, a mineral acid such as HCl is added to the reaction mixture duringthe reaction. The reaction pH is preferably maintained between 8.5 and10.5, more preferably between 9 and 10, most preferably between 9.5 and10. Between 30 minutes and 90 minutes after addition of the amine iscomplete, the reaction mixture becomes a homogeneous solution containingbretylium bromide, excess ethyldimethylamine, ethyldimethylammoniumsalts, e.g., ethyldimethylammonium bromide and ethyldimethylammoniumchloride, and water. It may also contain small amounts of 2-bromobenzylalcohol and unreacted 2-bromobenzyl bromide.

[0243] Preparation of Bretylium Salt of Interest

[0244] Ethyldimethylamine and most of the water is removed from thereaction mixture by evaporation under vacuum. A concentrated aqueoussolution of bretylium bromide and chloride is left behind, as thebretylium salts are nonvolatile.

[0245] An alkali metal salt of the hydrophobic or weakly hydrophilicanion, (e.g. sodium dodecylsulfate, sodium lauryl sulfate, potassiumsalicylate or potassium di(2-ethylhexyl)sulfosuccinate) is added to theconcentrated solution of bretylium salts, along with a water-immiscibleorganic solvent, e.g., chloroform (or any equivalent, such as methylenechloride or diethylether), and a minimum amount of distilled waternecessary to facilitate isolation of the quaternary ammonium salt of themore hydrophobic anion by transfer of salts between aqueous and organicphases. Preferably, from 0.5 to 2.0 moles of the hydrophobic anion areadded per mole of bretylium salt, more preferably from 0.8 to 1.5 molesof the hydrophobic anion are added, and most preferably from 1.1 to theanion is added.

[0246] Preferably, water is added in a ratio from about zero to twotimes the weight of the concentrated solution of the bretylium salts,more preferably from 0.5 to 1.5 times and most preferably from 0.8 to1.2 times. Preferably, the organic extractant, e.g., chloroform, isadded in a proportion from 3 to 30 times the weight of the concentratedsolution of bretylium salts, more preferably from 5 to 20 times, andmost preferably from 8 to 12 times the weight of the concentratedbretylium salts.

[0247] A two phase liquid-liquid mixture results. The mixture isagitated vigorously and then allowed to separate. The bretylium salt ofinterest concentrates in the chloroform phase and the alkali metalhalide concentrates in the aqueous phase. Partition coefficients in sucha system, defined as [bretylium(aqueous)]/[bretylium(chloroform)], areconservatively estimated to be about greater than 10.

[0248] The water phase is decanted off the organic extract phase. A highvolatility solvent such as chloroform may be evaporated at a pressure ofabout one torr for 24 hours at room temperature. Next, the temperatureis increased, e.g., to 43 degrees Celsius in the case of chloroform, andthe evaporation is continued for about another hour. Other pressures andlengths of time may be used by those skilled in the art withoutoverheating the product to remove the solvent. The residue whichcontains the product is a very viscous, colorless cloudy liquid.

[0249] The purity of the salt can be determined spectrophotometrically.Preferably yields should be greater than 50%, more preferably greaterthan 70% and most preferably greater than 85%.

[0250] DEFINITIONS

[0251] The term “hydrocarbyl” refers to a group composed of carbon andhydrogen. This definition includes alkyl, alkenyl, and alkynyl groupswhich are each straight chain, branched chain, or cyclic hydrocarbonstypically having from 1 to about 30 carbons atoms. Also included in thisdefinition are aryl groups composed of carbon and hydrogen. Hydrocarbyltherefore includes, for example, methyl, ethyl, propyl, butyl, pentyl,hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylcyclopentyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl,ethyne, propyne, butyne, pentyne, hexyne, phenyl, naphthyl, anthracenyl,benzyl, and isomers thereof.

[0252] The term “substituted hydrocarbyl” refers to a hydrocarbyl groupin which one or more hydrogen has been substituted with aheteroatom-containing group. Such substituent groups include, forexample, halo, oxo, heterocycle, alkoxy, hydroxy, aryloxy, —NO₂, amino,alkylamino, or amido. When the substituent group is oxo, the substitutedhydrocarbyl can be, for example, an acyl group.

[0253] The term “alkyl” refers to linear or branched hydrocarbon groupshaving from 1 to about 30 carbon atoms. Examples of such groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, pentyl, iso-amyl, hexyl, dodecyl, and the like. It should berecognized that such a group may be, for example, a residue of asaturated fatty acid formed by removing the carboxylic acid group fromthe fatty acid. More preferred alkyl groups are alkyl groups comprisingat least 6 carbon atoms.

[0254] The term “alkenyl” embraces linear or branched hydrocarbon groupshaving at least one carbon-carbon double bond, and from 2 to about 30carbon atoms. Examples of alkenyl groups include ethenyl, allyl,propenyl, butenyl, 4-methylbutenyl, and the like. The term “alkenyl”embraces groups having “cis” and “trans” orientations, or,alternatively, “E” and “Z” orientations. It should be recognized thatsuch a group may be, for example, a residue of an unsaturated fatty acid(having one or more double carbon-carbon bonds) formed by removing thecarboxylic acid group from the fatty acid. More preferred alkenyl groupsare alkyl groups comprising at least 6 carbon atoms.

[0255] The term “alkynyl” refers to linear or branched hydrocarbongroups having at least 1 carbon-carbon triple bond, and from 2 to about30 carbon atoms. Examples of alkynyl groups include propargyl,1-propynyl, 2-propynyl, 1-butyne, 2-butynyl, 1-pentynyl, and the like.More preferred alkyl groups are alkynyl groups comprising at least 6carbon atoms.

[0256] The term “cycloalkyl” refers to saturated carbocyclic hydrocarbongroups having 3 to about 30 carbon atoms. Examples of such groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.More preferred cycloalkyl groups are “lower cycloalkyl” groups havingfrom 3 to about 8 carbon atoms.

[0257] The term “cycloalkenyl” refers to partially unsaturatedcarbocyclic hydrocarbon groups having from 3 to about 30 carbon atoms.Examples of such groups include cyclobutenyl, cyclopentenyl,cyclohexenyl, and the like. More preferred cycloalkenyl groups are“lower cycloalkenyl” groups having from 4 to about 8 carbon atoms.

[0258] The term “aryl” refers to aromatic groups such as phenyl,naphthyl, tetrahydronaphthyl, indanyl, and biphenyl. The preferred arylis phenyl. Aryl moieties may also be substituted at a substitutableposition with one or more substituents selected independently fromalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and the like. Theterm “aryl, alone or in combination” refers to a carbocyclic aromaticsystem containing 1, 2, or 3 rings, wherein such rings may be attachedtogether in a pendent manner or may be fused.

[0259] The term “arylalkyl” refers to aryl-substituted alkyl groups suchas benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, anddiphenylethyl. The aryl in the aralkyl may be additionally substitutedwith one or more substituents selected independently from alkyl,alkenyl, alkynyl, cycloalkyl, and cycloalkenyl. The terms “arylalkenyl”and “arylalkynyl” are defined in a comparable manner.

[0260] The term “pharmaceutically acceptable” means being compatiblewith the other components of the composition or kit being administered,and not deleterious to the intended recipient of the composition or kit.

[0261] The term “pharmaceutically-acceptable salts” refers to salts suchas alkali metal salts, and common salts of free acids or free bases. Thenature of the salt is not critical, provided that it ispharmaceutically-acceptable. Suitable pharmaceutically-acceptable saltsof the bretylium cation and/or facilitating anion may be prepared froman inorganic acid or an organic acid. Examples of such inorganic acidsare hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric,and phosphoric acid. Appropriate organic acids may be selected fromaliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl,carboxylic, and sulfonic classes of organic acids (e.g., formic, acetic,propionic, succinic, glycolic, gluconic, lactic, malic, tartaric,citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic,glutamic, benzoic, anthranilic, mesylic, stearic, salicylic,p-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, β-hydroxybutyric, galactaric, andgalacturonic acid). Suitable pharmaceutically-acceptable salts of thesecompounds include metallic salts and organic salts. More preferredmetallic salts include, but are not limited to, appropriate alkali metal(group IA) salts, alkaline earth metal (group IIA) salts, and otherphysiologically acceptable metals. Such salts can be made from aluminum,calcium, lithium, magnesium, potassium, and sodium. Preferred organicsalts can be made from amines and quaternary ammonium salts, including,in part, trimethylamine, diethylamine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methylglucamine), and procaine.

[0262] The term “ventricular fibrillation threshold” refers to thelowest current level that, when applied to the heart, causes sustainedventricular fibrillation.

[0263] The term “effective ventricular refractory period” refers to theperiod during which the heart cannot be stimulated to contract by asuper threshold electrical stimulus.

[0264] The term “rate-corrected Q-T_(c) interval” refers to the intervalbetween the Q wave and the T wave, corrected for heart rate.

[0265] The term “prevent” means to at least partially suppress the onsetof a condition.

[0266] With reference to the use of the word(s) “comprise” or“comprises” or “comprising” in this entire specification (including theclaims below), Applicants note that unless the context requiresotherwise, those words are used on the basis and clear understandingthat they are to be interpreted inclusively, rather than exclusively,and that Applicants intend each of those words to be so interpreted inconstruing this entire specification.

EXAMPLES

[0267] The following examples are simply intended to further illustrateand explain the present invention. This invention, therefore, should notbe limited to any of the details in these examples. The symbols andconventions used in these examples are consistent with those used in thecontemporary pharmacological literature.

[0268] Unless otherwise stated, the pharmaceutical grade bretyliumtosylate used in these examples was obtained from Ganes Chemicals, Inc.,Carlstadt, N.J. The facilitating anions used in these examples arecommercially available or may be prepared as discussed above.

Example 1

[0269] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: INGREDIENT WEIGHT PERCENT¹bretylium cations 0.5% to 50% facilitating anions 0.5% to 50%neutralizing agent  15% to 99%

Example 2

[0270] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: INGREDIENT WEIGHT PERCENT¹bretylium cations   1% to 30% facilitating anions 1.7% to 30%neutralizing agent  50% to 98%

Example 3

[0271] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium tosylate 500 0.095 (0.056 for bretylium cationalone) sodium di(2-ethylhexyl) 536 0.102 sulfosuccinate (0.097 fordi(2-ethylhexyl) sulfosuccinate anion alone) sodium bicarbonate 4200 0.802

Example 4

[0272] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium tosylate 1275 0.275 (0.161 for bretylium cationalone) sodium di(2-ethylhexyl) 1367 0.294 sulfosuccinate (0.279 fordi(2-ethylhexyl) sulfosuccinate anion alone) sodium bicarbonate 20000.431

Example 5

[0273] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium tosylate 1275 0.214 (0.126 for bretylium cationalone) sodium salicylate  485 0.081 (0.069 for salicylate anion alone)sodium bicarbonate 4200 0.705

Example 6

[0274] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium di(2-ethyl- 3600 0.643 hexyl)sulfosuccinate (0.235for bretylium cation alone) (0.408 for di(2-ethylhexyl) sulfosuccinateanion alone) sodium bicarbonate 2000 0.357

Example 7

[0275] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium di(ethylhexyl) 3600 0.545 sulfosuccinate (0.2 forbretylium cation alone) (0.345 for di(2-ethylhexyl) sulfosuccinate anionalone) sodium bicarbonate 2000 0.303 citric acid 1000 0.152

Example 8

[0276] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium salicylate 2000 0.4 (0.241 for bretylium cationalone) (0.159 for salicylate anion alone) sodium bicarbonate 2000 0.4citric acid 1000 0.2

Example 9

[0277] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: AMOUNT INGREDIENT (mg) WEIGHTFRACTION¹ bretylium tosylate 120 0.261 (0.153 for bretylium cationalone) sodium di(2-ethylhexyl) 130 0.283 sulfosuccinate (0.268 fordi(2-ethylhexyl) sulfosuccinate anion alone) sodium citrate 200 0.435protriptyline  10 0.022

Example 10

[0278] A pharmaceutical composition was prepared having the followingcomposition: AMOUNT INGREDIENT (mg) WEIGHT FRACTION¹ bretylium tosylate12,000 0.021 (0.012 for bretylium cation alone) aspirin  5,000 0.009(0.008 for acetylsalicylate anion alone) sodium citrate 50,000 0.088water 500,000  0.882 (500 ml)

[0279] Generally, sodium citrate is not necessary when administeringthis composition parenterally (e.g., by continuous infusion over anappropriate period). Alternatively, the composition can be furtherdivided into suitable unit oral dosage forms (e.g., unit dosage formscontaining 120 mg of bretylium tosylate), and orally administered.

Example 11

[0280] An oral pharmaceutical composition was prepared having thefollowing composition: WEIGHT INGREDIENT AMOUNT (mg) FRACTION¹ bretyliumdi(2-ethylhexyl) 500 0.926 sulfosuccinate protriptyline  40 0.074 waterAn amount sufficient to provide a total final volume for the solution of50 ml

Example 12

[0281] A pharmaceutical composition suitable for oral administration wasprepared having the following composition: INGREDIENT WEIGHT PERCENT¹bretylium cations 0.5% to 64% facilitating anions 0.3% to 63%neutralizing agent 0.02% to 99% 

Example 13 Determination of Partition Coefficients

[0282] Several formulations of the present invention were tested usingan n-octanol/aqueous buffer system to measure the partition coefficientsfor the bretylium cation in the presence of the facilitating anions ofthose formulations. An acidified aqueous solution of bretylium tosylatewas first prepared. Sodium bicarbonate and a salt comprising thefacilitating anion to be tested was then added to the aqueous solution.The salt comprising the facilitating anion was added in an amountsufficient to provide a 1:1 molar ratio of the facilitating anion to thebretylium cation. The sodium bicarbonate was provided in an amountsufficient to produce one of 4 preselected pH values. An equal volume ofn-octanol was then added to this solution and the solution was shaken.The mixture was centrifuged to separate an octanol layer and an aqueouslayer, and the distribution ratio of the bretylium cation between theoctanol-rich phase and the aqueous-rich phase (that is, the partitioncoefficient) was measured. This analytical approach provides a suitablemodel for evaluating the bioavailability of the bretylium cation in thecompositions tested.

[0283] A. Preparation of Aqueous Bretylium Tosylate Solution

[0284] The aqueous bretylium tosylate solutions used in the procedurewere prepared in the following manner. An amount of one of the buffersolutions described below (3.0 ml when the most acidic buffer solutionwas used, and 4.0 ml when the other 3 buffer solutions were used) wastransferred to a beaker or an Erlenmeyer flask by pipette. To the buffersolution was added 50 mg of bretylium tosylate per ml of buffer solutionand an equimolar amount of the sodium salt of the facilitating anion.For example, where the facilitating anion tested wasdi(2-ethylhexyl)sulfosuccinate, 54 mg of sodiumdi(2-ethylhexyl)sulfosuccinate was added per ml of buffer solution.Where the facilitating anion tested was salicylate, 19 mg of sodiumsalicylate was added per ml of buffer solution. Test solutionscomprising other facilitating agents were prepared in a similar manner.

[0285] B. Preparation of Sodium Bicarbonate Buffer Solutions

[0286] Each of the pharmaceutical compositions was tested using each ofthe following sodium bicarbonate buffer systems:

[0287] The first buffer solution was prepared by dissolving 1.0 g ofsodium bicarbonate in 100 ml of 0.95M HCl. A pH meter equipped with aconventional glass electrode and a calomel reference electrode was usedto measure the nominal pH of this solution and the other 3 buffersolutions. The nominal pH measured for the first solution was 0.8.Because the glass electrode probably is not able to respond adequatelyto such an acidic solution, it is likely that the actual pH of thissolution was lower, perhaps slightly negative. The nominal pH of thissolution, however, was reproducible.

[0288] The second buffer solution was prepared by dissolving 7.5 g ofsodium bicarbonate in 100 ml of 0.95M HCl. This solution had areproducible nominal pH of 2.2, slightly higher than the expected pH ofabout 2.0.

[0289] The third buffer solution was prepared by dissolving 8.0 g ofsodium bicarbonate in 100 ml of 0.95M HCl. This solution had a nominalpH between about 5.0 and about 6.0. While the pH meter is reliable inthis pH range, the pH was somewhat variable because the solution hadminimal buffer capacity.

[0290] The 4th buffer solution was prepared by dissolving 10.0 g ofsodium bicarbonate in 100 ml of 0.95M HCl. This solution had areproducible nominal pH of 7.7 that likely is close to the actual pH ofthe solution.

[0291] The first buffer solution was intended to model the acidity ofthe aqueous contents of the human stomach. The other 3 buffer solutionswere intended to model the aqueous contents of the stomach afteradministration of an amount of sodium bicarbonate to reduce the acidityof the stomach.

[0292] C. Facilitating Anions Tested

[0293] The sodium salts of the following facilitating anions weretested: di(2-ethylhexyl)phosphate, di(2-ethylhexyl)sulfosuccinate,lauryl sulfate, and salicylate. All these salts were commerciallyavailable from Aldrich Chemical, Milwaukee, Wis. and/or Ecolab, Inc.,St. Paul Minn. Each of the 4 facilitating anions was tested in each ofthe 4 buffer systems.

[0294] D. Preparation and Equilibration of n-Octanol/Buffer Systems

[0295] A 1.0 ml aliquot of the formulated aqueous test solution wasadded to 1.0 ml of n-octanol (Aldrich Chemical Co., HPLC grade, 99%purity), and the mixture was shaken for 30 seconds. The n-octanol andaqueous phases, which are not miscible, were separated by centrifugingat about 3000 rpm for about 10 minutes or until clarification wasachieved. The phases were physically separated and the bretyliumconcentration of each phase was determined as described below. Thisprocedure was followed for each combination of facilitating anion andbuffer system. In addition, a corresponding control test was carried outwithout a facilitating anion in each of the buffer systems.

[0296] E. Measurement of Partition Coefficient

[0297] The concentration of the bretylium cation in the separatedn-octanol and aqueous phases was determined by spectrophotometry usingthe long wavelength absorption of the bretylium cation at 270 nm. Thisband is due to the benzene chromophore of the bretylium cation.

[0298] To determine the concentration of bretylium in the octanol phase,each n-octanol phase sample obtained as above was diluted with an equalvolume of pure n-octanol. The resulting n-octanol solution was thenequilibrated with 1.5 times its own volume of 3 M HCl to protonate theacid of any acid weaker than HCl that was present. Because bretyliumchloride is very water soluble but only sparingly soluble in n-octanol,it is extracted into the aqueous phase in high yield. The absorbance ofthe resulting aqueous phase at 270 nm was then determinedspectrophotometrically. The protonated former facilitating anion (whichotherwise might contribute to the absorbance) was converted to itsneutral conjugate acid by the HCl and remained in the n-octanol phase.For example, if the bretylium cation is present as a tosylate in theoctanol phase, then acidification largely converts the tosylate anion totoluenesulfonic acid, an acid preferentially soluble in the n-octanolphase. Accordingly, the facilitating anion is not transferred to theaqueous phase with the bretylium chloride and does not contribute to themeasured absorbance. The chloride anion is present in the aqueous phasebut is free of absorbance in the region of interest.

[0299] To determine the concentration of bretylium in the aqueous phase,each aqueous phase sample obtained as above was mixed with twice its ownvolume of 5M HCl and the resulting aqueous solution was thenequilibrated with a volume of n-octanol equal to twice the originalaqueous phase sample volume. The HCl protonated the facilitating anionand any other anions of acids weaker than HCl that were present andmight contribute to the absorbance if allowed to remain in solution. Theunwanted anions were extracted into the n-octanol phase as theirconjugate acids. The absorbance of the aqueous phase, after then-octanol extraction, was determined spectrophotometrically at 270 nm.

[0300] Test solutions exhibiting a measured absorbance greater than 1.2were diluted with water so as to provide an absorbance between 0.040 and1.2 and then re-measured. This dilution was employed to providebretylium concentrations within the concentration range in whichabsorbance could be reliable measured. In such cases, the absorbance ofthe diluted test solution was then multiplied by a dilution factor todetermine the true absorbance of the original test solution.Alternatively, the original separated aqueous solution and thecorresponding original separated n-octanol solution were diluted by thesame factor so as to cancel out the dilution factor during thecalculation of the partition coefficient.

[0301] Dilution occurs whenever additional solvent is added to asolution of an analyte, or the analyte is transferred to a new solutionof greater volume than its original volume. Such increases in volume mayoccur for reasons of convenience, or because the parameter to bemeasured (e.g., absorbance) is above the optimal range of instrumentalaccuracy. The dilution factor is the final volume divided by the initialvolume. If several dilutions have been made the dilution factors aremultiplicative. For example, if the original aqueous test sample was 1.0ml (as in the present case) and the bretylium ion is recovered in 1.5 mlof aqueous acid, the dilution factor is 1.5. If the absorbance of thissolution is too high for accurate measurement, and 0.3 ml of thissolution is diluted with 5 ml of water, a second dilution has occurredwith a dilution factor of 17.7 (that is, 5.3/.3). The overall dilutionfactor is 26.5 (that is, 17.7×1.5). To determine the absorbance of theoriginal solution, which is proportional to its bretylium concentration,the absorbance of the final solution is multiplied by the overalldilution factor (26.5 in the illustrative example). The proportionalityconstant that converts absorbance to the molar concentration of thebretylium cation is the molar absorbance.

[0302] In the present case, the ratio of the bretylium concentration inthe octanol phase to the bretylium concentration in the aqueous phase(i.e., the partition coefficient) is needed. When the 2 overall dilutionfactors are the same, then the ratio of concentrations is equal to theratio of observed absorbances. When the 2 overall dilution factors arenot the same, then the ratio of observed absorbances times the ratio ofdilution factors equals the ratio of concentrations. The analyticalscheme described above has the advantage that all absorbances aremeasured in aqueous solution, so that the molar absorbance is constant.

[0303] The partition coefficients calculated from the measuredabsorbances are set forth in Table 1A below. These test results confirmthat the partition coefficient (and, thus, the bioavailability) oforally administered bretylium cations can be increased—in some cases upto nearly 10-fold—by using suitable a facilitating anion and/or aneutralizing agent in combination with the bretylium cation. Whileincreasing the pH of the test solution alone increased partitioncoefficient values, increasing the pH of the solution in combinationwith the addition of a suitable facilitating anion resulted in anadditional increase in partition coefficient values in all cases.Similarly, use of certain facilitating anions in combination with thebretylium cation without a concurrent increase in the pH of the testsolution materially increased partition coefficient values, particularlyfor the sulfate and sulfosuccinate facilitating anions tested. Thephosphate and salicylate facilitating anions tested, however, generallyperformed better and provided higher partition coefficient values as thepH of the test solution increased. TABLE 1A PARTITION NOMINAL pHFACILITATING ANION COEFFICIENT 0.8 None 0.33 2.1 None 0.48 5.5 None 0.457.7 None 0.49 0.8 di(2-ethylhexyl)phosphate 0.35 2.2di(2-ethylhexyl)phosphate 0.49 5.5 di(2-ethylhexyl)phosphate 0.51 7.7di(2-ethylhexyl)phosphate 2.33 0.8 di(2-ethylhexyl)sulfosuccinate 2.192.2 di(2-ethylhexyl)sulfosuccinate 2.52 5.5di(2-ethylhexyl)sulfosuccinate 4.16 7.7 di(2-ethylhexyl)sulfosuccinate3.61 0.8 lauryl sulfate 1.91 2.2 lauryl sulfate 3.54 5.5 lauryl sulfate3.71 7.0 lauryl sulfate 4.01 0.8 salicylate 0.56 2.2 salicylate 1.31 5.5salicylate 1.31 7.0 salicylate 1.90

[0304] F. Control Experiments

[0305] Two series of control experiments were conducted to furthervalidate the above procedure. In the first series of experiments, themolar absorbance of bretylium in the absence of a facilitating anion wasmeasured at 2 different initial concentrations. Bretylium tosylate in anamount of 150 mg was added to 3.0 ml of water. This solution was thenacidified with HCl, extracted with octanol, and diluted in accordancewith the procedure described above. The experiment was repeated using aninitial aqueous solution that was 100 times more dilute. The molarabsorbance was calculated for each solution by dividing its absorbanceafter extraction by its initial concentration. The results are reportedin Table 1B below. TABLE 1B INITIAL BRETYLIUM MOLAR TOSYLATE ABSORBANCECONCENTRATION (moles/L) ABSORBANCE¹ (L/mole) 1.21 × 10⁻¹ 43.0 355 1.21 ×10⁻³ 0.39 326

[0306] The consistency of the molar absorbance over 2 orders ofmagnitude of initial concentration shows that the measured absorbance,corrected for dilution, is proportional to the bretylium concentration,as indicated.

[0307] In the second series of experiments, the procedure was testedusing a solution containing the salicylate facilitating anion, but notthe bretylium cation. To the second buffer solution (prepared asdescribed above) was added a sufficient amount of sodium salicylate andtetrabutylammonium bromide to provide a 0.21 M sodium salicylate/0.12 Mtetrabutylammonium bromide solution. Tetrabutylammonium bromide was usedas a phase transfer agent to mimic the bretylium cation and ensure thetransfer of a substantial amount of salicylate anion to the n-octanolphase. The solution was divided into 3 portions of about 0.7 g each, and1.0 g of n-octanol was added to each of the 3 solutions. The solutionswere shaken for about 30 seconds and then centrifuged at about 3000 rpmfor about 5 minutes to clarify both phases. About 0.7 g of eachn-octanol phase was removed and weighed and an equal weight of 5 M HClwas added to each n-octanol sample. The new 2-phase systems were shaken(about 30 seconds), and separated by centrifugation (3000 rpm for about5 minutes) to produce clear solutions. The absorbance of these solutionsat 270 nm was measured. This procedure was also carried out using thethird and 4th buffer solutions (prepared as described above). Theresults are disclosed in Table 1C below. TABLE 1C FINAL AQUEOUS FINALOCTANOL ORIGINAL pH ABSORBANCE ABSORBANCE 2.1 0.049 1.095 5.5 0.0470.814 7.7 0.056 0.828

[0308] The sodium cation is nearly free of absorbance in the region ofinterest. Although the salicylate anion and salicylic acid absorb lightin the ultraviolet region, they do not exhibit absorption maxima at ornear the 270 nm absorption region of the bretylium cation. The resultsreported in Table 1C indicate that only about 5 to 6% of the salicylateanion/salicylic acid is transferred to the final aqueous HCl solutions.The absorbance at 270 nm resulting from the transferred salicylateanion/salicylic acid is not materially significant when compared to theabsorbance measured for the bretylium cation using the procedurediscussed above. The combination of minimal absorbance at 270 nm and theextraction of salicylic acid into the octanol phase ensures thatsalicylate does not materially interfere with the determination of thebretylium concentration in accordance with the procedure describedabove.

Example 14 Effect of Facilitating Anion Concentration on the PartitionCoefficient

[0309] The procedure of Example 13 was repeated for thedi(2-ethylhexyl)sulfosuccinate and salicylate facilitating anions using2 moles of facilitating anions per mole of bretylium tosylate instead ofequimolar amounts as in Example 13. The partition coefficient resultsobtained are set forth in Table 2A below: TABLE 2A PARTITION NOMINAL pHFACILITATING ANION COEFFICIENT 0.8 di(2-ethylhexyl)sulfosuccinate 3.582.2 di(2-ethylhexyl)sulfosuccinate 4.98 5.6di(2-ethylhexyl)sulfosuccinate 4.94 7.0 di(2-ethylhexyl)sulfosuccinate5.03 0.8 salicylate 1.06 2.2 salicylate 1.52 5.5 salicylate 1.61 7.0salicylate 2.36

[0310] These results indicate that increasing the molar ratio offacilitating anion to bretylium cation can materially increase the valueof the partition coefficient.

Example 15 Effect of the Facilitating Anion on Bretylium Efficacy

[0311] The increase in efficacy and bioavailability of the bretyliumcation afforded by the formulations of the present invention was testedby orally administering formulations containing bretylium cations anddi(2-ethylhexylsulfosuccinate) anions to male beagle dogs weighingapproximately 10 kg, and subsequently measuring the ventricularfibrillation threshold (VFT), effective ventricular refractory period(EVRP), and rate-corrected Q-T_(c) interval of the dogs.

[0312] A formulation was orally administered to each dog in 3 divideddoses in capsule form (i.e., conventional gelatin capsule). Each capsulecontained 120 mg of bretylium tosylate; 120 mg of sodiumdi(2-ethylhexylsulfosuccinate); and 300 mg of sodium bicarbonate. The 3capsules were administered to each dog over a period of 8 hours toachieve a bretylium tosylate total loading dose of approximately 36 mgper kg of body weight. The second capsule was administered 4 hr afterthe first capsule, and the third capsule was administered 8 hr after thefirst capsule.

[0313] Ten hours after administration of the first capsule, each dog wasanesthetized by injection with 300 mg/kg pentabarbital (animal hospitalsupply grade). Additional doses of pentabarbital were administered asneeded when the dogs started to awaken. The heart of each dog wasexposed via an intercoastal approach, and the pericardium was opened.Stimulating bipolar silver-silver-chloride electrodes embedded in epoxyand recording electrodes were sewn to the right ventricular surface ofeach dog. The femoral artery was canulated to measure blood pressure.

[0314] The ventricular fibrillation threshold, effective ventricularrefractory period, and rate-corrected Q-T_(c) interval of each dog weremeasured at various times during the 10-hour interval afteradministration of the third capsule. Electrical ventricular fibrillationthresholds were determined using a Grass Instruments Company constantcurrent unit to initiate a gated train of 60 Hertz impulses of 2millisecond duration via the pair of stimulating electrodes sewn intothe surface of the right ventricle. The current train began immediatelyafter ventricular activation to cover the vulnerable period during whichventricular fibrillation can be electrically induced. The stimulusstrength began at 2.5 mamp, and was increased in 2.5 mamp steps untilsustained ventricular fibrillation was induced. The heart was thenelectrically defibrillated. Subsequently, at least 1 hr was allowed forrecovery and drug actions to increase before the ventricularfibrillation threshold was measured again. After each ventricularfibrillation threshold, the effective ventricular refractory period wasdetermined. The rate-corrected Q-T_(c) interval was measured from theelectrocardiogram. Effective ventricular refractory period wasdetermined by establishing the earliest time that a stimulus deliveredafter ventricular activation could elicit another contraction.Rate-corrected Q-T_(c) interval was measured from a high speedelectrocardiographic trace.

[0315] The ventricular fibrillation threshold, effective ventricularrefractory period, and rate-corrected Q-T_(c) interval values measuredin the dogs are set forth in Table 3A: TABLE 3A TIME RATE-COR- AFTERRECTED LAST Q-T_(c) DOSE VFT EVRP INTERVAL SUBJECT (hr) (mamp) (msec)(sec) Untreated Dog N/A  5.0 135 270  (Average Value) Dog 1: 2.75 >50(50 milliamps 205 408¹ was the maximum available current) 5 42.5 223388¹ 8 30¹  220 380¹ 10  24.5 224 374¹ Dog 2: 2 >50    219 400  5 40¹ 208 388¹ 10 25¹  224 374¹

[0316] These results show an increase in ventricular fibrillationthreshold for the dogs, and, therefore, confirm that the formulations ofthe present invention increase the bioavailability of orallyadministered bretylium tosylate. In fact, fibrillation of the heart ofthe dogs could not be induced until about 6 hr after administration ofthe third loading dose capsule. After about 6 hr, the heart could befibrillated with a 50 mamp current train, but the heart spontaneouslydefibrillated either once the current train was terminated or after asingle low current defibrillation shock was applied. The time intervalover which the increase in ventricular fibrillation threshold, effectiveventricular refractory period, and rate-corrected Q-T_(c) interval wasobserved further suggests that a once or twice-a-day dosage of theformulations can suffice after the therapeutic concentration has beentaken up by the binding sites in the heart.

Example 16 Effect of Various Facilitating Anions on Bretylium Efficacy

[0317] The increase in efficacy and bioavailability of the bretyliumcation afforded by the formulations of the present invention werefurther tested by orally administering either 1 or 2 doses of variousbretylium-tosylate/facilitating-anion combinations (all containingroughly an equimolar amount of bretylium tosylate and the facilitatinganion), and then measuring the ventricular fibrillation threshold of thedogs at various times following the oral administration.

[0318] Mongrel dogs of either sex and weighing from about 10 to about 40kg were used. The dogs were anesthetized with isofluorine gas andrespired with a Harvard respirator using room air. A catheter electrodewas passed under fluoroscopic observation via the jugular vein into theapex of the right ventricle and screwed into place in the myocardium ofthe right ventricle.

[0319] The ventricular fibrillation threshold (VFT) was determined usinga Grass Instruments Company constant current unit to initiate a gatedtrain of 60 Hertz impulses of 1 millisecond duration. The current trainbegan immediately after ventricular activation and was sustained longenough to cover the vulnerable period during which ventricularfibrillation can be electrically induced. The stimulus strength began at5 milliamps, and was increased in 3-4 milliamp steps until sustainedventricular fibrillation was induced (or until the maximum current of 50milliamps was applied).

[0320] After the control VFT and EVRP were measured, the compositionswere orally administered in capsule form via a stomach tube. Here, thecapsule was pushed by a rod into the stomach tube, and then washed intothe stomach with 50 ml glucose delivered through the stomach tube. TheVFT and EVRP were measured at various times following thisadministration. In some instances (i.e., Dogs 1, 3, & 4) a second oraldose was also given 12 hours after the first dose.

[0321] Table 4 shows the results (“BT” means bretylium tosylate, “NaS”means sodium salicylate, “NaLS” means sodium lauryl sulfate, “VFT” meansventricular fibrillation threshold, and “EVRP” means effectiveventricular refractory period). See also FIGS. 8-10. The effects of thebretylium were observed within 10 minutes of oral administration of thecompositions. In addition, within 30 minutes of oral administration, theventricular fibrillation threshold generally increased significantly.And, in many instances, the subject dogs eventually could not befibrillated at all, even at the maximum current of the generator (VFTvalues of greater than 50 milliamps in Table 4 represent instances wherethe subject could not be fibrillated at the maximum current (i.e., 50milliamps) of the generator). This effect on the ventricularfibrillation threshold generally continued over the entire 29 hourmeasuring period, thus suggesting that one dosage per day of thesecompositions is sufficient. TABLE 4 VFT After Drug Dose VFT EVRP SecondDrug Dose (VFT (mamp); EVRP After Drug Dose Before Drug Before Drug(administered at 12 hr % increase in VFT; (EVRP (msec); Dose Dose FirstDrug Dose after first drug dose) time of measurement time of measurementSubject (mamp) (msec) (per kg dog) (per kg dog) after first drug dose)after first drug dose) Dog 1 27 101  15 mg BT 10 mg BT >50; >85%; 24 hr195; 24 hr  10 mg NaLS  7 mg NaLS Dog 2 13 150  20 mg BT No Second Dose26; 100%; 1.25 hr 130; 1 hr  14 mg NaLS Dog 3 5 105  15 mg BT  5 mg BT19; 280%; 2 hr 125; 30 min  10 mg NaLS 10 mg NaLS 34; 580%; 24 & 25 hr134; 1.4 hr 36; 620%; 25.5 hr 138; 2 hr 33; 560%; 26 hr 141; 3 hr 132;24 hr 130; 25 hr 138; 25.5 hr 135; 26 hr Dog 4 19 98  15 mg BT  5 mgBT >50; >163%; 2 hr 104; 30 min  10 mg NaLS  5 mg NaLS 36; 89%; 24.5 hr110; 1 hr >50; >163%; 26 & 27 hr 108; 1.5 hr 112; 2 hr 128; 24.5 hr 111;26 hr 112; 27 hr Dog 5 16 96  15 mg BT No Second Dose >50; >213%; 2.3 &24 hr 107; 40 min   6 mg NaS 101; 2.3 hr 118; 24 hr Dog 6 15 100  15 mgBT No Second Dose >50; >233%; 30 min. 124; 13 min   6 mg NaS & 24 hr150; 24 hr Dog 7 27 115  15 mg BT No Second Dose >50; >85%; 10 min,1 hr,125; 10 min 6.5 mg aspirin 2.5 hr, & 29 hr 132; 1 hr 140; 1.5 hr 131; 29hr Dog 8 11 95  15 mg BT No Second Dose 48; 336%; 10 min 90; 3 min 6.5mg aspirin >50; >355%; 15 min, 97; 5 min 23 hr, & 23.25 hr 97; 10 min105; 15 min 138; 23 hr 116; 23.25 hr Dog 9 11 148  15 mg BT No SecondDose 23; 109%; 15 min 150; 15 min 6.5 mg aspirin 36; 228%; 30 min 138;30 min 35; 218%; 1 hr 140; 1 hr Dog 10 12 145  15 mg BT No Second Dose49; 308%; 1 hr 155; 1 hr 6.5 mg aspirin >50; >317%; 3 & 24 hr 155; 3 hr126; 24 hr Dog 11 11 164  15 mg BT No Second Dose 12; 9%; 22 min 165; 22min 6.5 mg aspirin >50; >355%; 2.25 & 205; 2.25 hr 25 hr 152; 25 hr Dog12 25 102  15 mg BT No Second Dose >50; >100%; 40 min & 102; 40 min 6.5mg aspirin 24.7 hr 107; 24.7 hr

Example 17 The Effect of the Compositions of This Invention on AtrialFibrillation

[0322] The effect of the compositions of this invention on atrialfibrillation was observed using a mongrel dog weighing approximately 35kg. Atrial fibrillation was initially induced by a stimulating bipolarelectrode catheter (to position this catheter electrode, it was passedinto the right atrium via the jugular vein under fluoroscopicobservation and then screwed into place in the myocardium of the rightatrium). This electrode catheter delivered stimulating shocks consistingof a train of square wave pulses of 1 msec duration at 60 Hz. Atrialfibrillation was induced at a current of 6 milliamps.

[0323] Defibrillation was first attempted using a single dose ofbretylium tosylate (Arnar-Stone, McGaw Park, Ill.) administeredintravenously (the dose corresponded to 15 mg of bretylium tosylate perkg of the recipient). No effect on atrial fibrillation was observed.

[0324] Subsequently, a composition containing bretylium tosylate andaspirin was administered intravenously into the jugular vein. Thiscomposition was prepared using a commercially available tabletcontaining aspirin. The aspirin tablet was dissolved in warm water andfiltered through a fine surgical gauze pad (to remove the bulk of thebinder in the tablet). The resulting aspirin filtrate was then combinedwith an approximately equimolar amount of bretylium tosylate dissolvedin 5% dextrose in water. Approximately 20 ml of this aqueous solutionwas injected into jugular vein of the atrially fibrillating dog (thisdose corresponded to roughly 15 mg of bretylium tosylate per kg of therecipient and 6.5 mg of aspirin per Kg recipient). FIG. 1 shows theelectrocardiogram for the dog following this administration. As can beseen, the atrial fibrillation was eliminated within 50 seconds of theadministration. And the fibrillation subsequently could not bere-induced even at the maximum generator current of 50 milliamp.

Example 18 Effect of β-Receptor Blocker on Bretylium Efficacy

[0325] The increase in efficacy of the bretylium cation afforded byadministering the bretylium cation in combination with a β-receptorblocker was tested by administering via injection bretylium tosylatealone, various β-receptor blockers alone, and various combinations ofbretylium tosylate and β-receptor blockers to dogs, and then measuringthe ventricular fibrillation threshold of the dogs 1-5 hours after drugadministration. Table 5 shows the results. TABLE 5 CompositionAdministered (per kg of recipient dog) Mean % Increase in VFT 20 mgbretylium tosylate 100-200% (no standard no β-receptor blocker deviationcalculated) 0.075 mg propranolol 110% ± 40%  no bretylium 0.05 mgpropranolol 320% ± 180% 20 mg bretylium tosylate 0.075 mg propranolol540% ± 360% 10 mg bretylium tosylate 0.25 mg propranolol 310% ± 70%  20mg bretylium tosylate 0.05 mg atenolol 330% ± 210% no bretylium 0.025 to0.1 mg atenolol 550% ± 430% 20 mg bretylium tosylate 0.05 mg metoprolol96% ± 70% no bretylium 0.035 mg metoprolol 410% ± 180% 10 mg bretyliumtosylate 0.05 mg metoprolol 410% ± 190% 10 mg bretylium tosylate 0.035to 0.1 mg metoprolol 370% ± 200% 10 mg bretylium tosylate 25 to 300 μgesmolol no significant increase no bretylium 200 μg esmolol 380% ± 150%10 mg bretylium tosylate 25 μg esmolol 290% ± 110% 10 mg bretyliumtosylate 25 μg esmolol 350% ± 180% 20 mg bretylium tosylate 300 μgesmolol 300% ± 190% 10 mg bretylium tosylate

[0326] In another experiment, the effect of a β-receptor blocker on thetiming and efficacy of the bretylium cation was observed:

[0327] Control #1: Administration of Bretylium Tosylate Alone

[0328] When bretylium tosylate alone was intravenously administered(using a dose of about 20 mg of bretylium tosylate per kg of caninerecipient), a substantial increase in the ventricular fibrillationthreshold began at 12-15 minutes after administration. About 3 hoursafter administration, this increase peaked at roughly 30 to 90 mamp,i.e., about 100 to 200% greater than the ventricular fibrillationthreshold where no bretylium was administered at all (i.e., roughly 10to 30 mamp).

[0329] Control #2: Administration of Propranolol Alone

[0330] When propranolol alone was intravenously administered (using adose of 0.05 to 0.5 mg/kg), there was a 110%±40% increase in theventricular fibrillation threshold.

[0331] Administration of Bretylium Tosylate and Propranolol

[0332] When a combination of bretylium tosylate and propranolol wasintravenously administered (using a dose of 20 mg/kg bretylium tosylateand 0.05 to 0.2 mg/kg propranolol) to 10 dogs, the ventricularfibrillation threshold increased to greater than 100 mamp (the maximumcurrent generator output) within 3 to 10 minutes of the administration,and the hearts of all 10 dogs remained non-fibrillatable for the entire6 hour study period after the administration.

Example 19 Administration of Bretylium Lauryl Sulfate in Capsule Form

[0333] The effect of the compositions of this invention on atrial andventricular fibrillation were observed using a mongrel dog weighingapproximately 35 kg.

[0334] At time zero, a 5 milliamp stimulus was applied and a ventricularfibrillation threshold (VFT) was established. FIG. 2 shows anelectrocardiogram of a dog chosen as a control having normal sinusrhythm. At 10 minutes, a 2 milliamp current was applied to attempt toestablish atrial fibrillation, but it was unsuccessful. At 12.53minutes, a dilute solution of aconitine was dabbed on the right surfaceof the atrium, which caused a brief burst of atrial tachycardia followedby sustained atrial fibrillation. FIG. 3 is an electrocardiogram of thedog taken immediately after the aconitine was painted on the atrium andFIG. 4 is an electrocardiogram of the dog showing sustained atrialfibrillation after a short burst of atrial tachycardia following theaconitine painting. The atrial fibrillation was sustained for a littleover an hour as demonstrated in FIGS. 5 and 6.

[0335] At 1 hour and 20 minutes, the dog was given a 50 mg/kg dose ofbretylium lauryl sulfate salt. Approximately 18 minutes after the dose(1 hour and 38 minutes into the experiment), periods of a normal sinusrhythm were observed as demonstrated in FIG. 7. Atrial fibrillationceased entirely 19 minutes after the dose was applied (1 hour and 39minutes into the experiment).

[0336] At three hours and twenty minutes, the dog's left anteriorcoronary artery was ligated to attempt to induce ventricularfibrillation by coronary occlusion. No ventricular fibrillation wasobserved. After three hours and thirty five minutes, the occlusion wasreleased, and again, no ventricular fibrillation was observed for thefollowing two minutes.

[0337] Next, at three hours and thirty-seven minutes, 50 milliamps (themaximum current) was applied in an attempt to induce ventricularfibrillation and/or atrial fibrillation. No fibrillation (atrial orventricular) could be induced by electrical stimulation.

[0338] Thus, the current invention provides protection against coronaryligation and reperfusion, electrical fibrillation and chemicalstimulation (aconitine).

Example 20 Method of Making Bretylium Dodecylsulfate

[0339] A concentrated aqueous solution of bretylium bromide may beprepared by treating 2-bromobenzyl bromide with ethyldimethylamine inthe presence of aqueous sodium bicarbonate. The sodium salt of thehydrophobic or weakly hydrophilic anion is then added to the aqueousbretylium bromide solution, and then the required bretylium salt isextracted from the aqueous solution or else is dispersed with asuitable, water-insoluble solvent. The nonaqueous solution is dehydratedand solvent is evaporated under vacuum, leaving the nonvolatile, desiredbretylium salt.

[0340] A. Preparation of Bretylium Bromide

[0341] 25 g (0.1 moles) of 2-bromobenzyl bromide was added to 100 ml ofdistilled water in a 250 ml 3-necked round bottom flask, fitted with apH probe (combined glass electrode and calomel reference electrode) athermometer, and an addition funnel. A two phase mixture was obtained.To this mixture, 29.2 g (0.4 moles) of ethyldimethylamine were added insmall portions. After each portion of amine was added, a small quantityof 10 M HCl was added, so as to maintain the pH at a value between 9 and10. (Ethyldimethylamine has a pK of approximately 10. At a pH below 9,almost all of the amine would be protonated, slowing the reaction. At apH above 10, the hydrolysis of 2-bromobenzyl bromide by hydroxide to2-bromobenzyl alcohol is accelerated, without much acceleration of theproduct-forming reaction.)

[0342] Thirty-eight minutes after the addition was completed, themixture became a homogeneous solution. Since 2-bromobenzyl bromide isalmost completely water-insoluble, it was assumed that reaction wascomplete. (Ethyldimethylamine is water-soluble.) The total volume of thefinal solution was 130 ml, so the concentration of bretylium bromide was0.77 upon full completion of the reaction. This solution may alsocontain some excess, unreacted ethyldimethylamine and someethyldimethylammonium bromide.

[0343] B. Preparation of Bretylium dodecylsulfate

[0344] Bretylium dodecylsulfate was prepared as an example of thepreparation of bretylium salts of hydrophobic or weakly hydrophilicanions. A 25.5 g sample of the bretylium bromide solution prepared abovewas mixed under vacuum in a rotary evaporator, reducing its mass to 7.48g by evaporation. The removed, volatile material was ethyldimethylamineand water. Bretylium bromide is nonvolatile. This material containsapproximately 2.6 mmoles of bretylium bromide per gram, based on theoriginal concentration. To 2.0 g of this material (5.2 mmoles ofbretylium bromide) were added 2.0 g (6.2 mmoles) sodium dodecylsulfate,2.0 g of distilled water, and 19 g of chloroform. A two phase mixtureresulted. This was agitated vigorously, then allowed to separate.Previous distribution experiments suggested that bretyliumdodecylsulfate would be concentrated in the chloroform phase, and sodiumbromide in the aqueous phase. The chloroform was evaporated at about onetorr; first, for 24 hours, at room temperature; then, at 43° C. for onehour. The residue was 1.7 g of very viscous, colorless, cloudy liquid(3.4 mmoles as bretylium dodecylsulfate, 65% yield).

[0345] To confirm the identity of the isolated material, its absorbanceat 270 nm was compared with the known absorbance of the bretylium ion.The dodecylsulfate ion has no absorbance at this wavelength. 63 mg ofproduct was dissolved in 10.28 g of distilled water and 1.0 g of thissolution was diluted to 13.67 g with distilled water. If the product isbretylium dodecylsulfate this should give an 0.00088 M solution. Usingthe previously determined molar absorption coefficient for the bretyliumion, 350, an absorbance of 0.307 is predicted for this solution in acell of 1.00 cm path length. The measured absorbance was 0.329. Thisagreement is considered a good confirmation of the identity of thematerial. The small excess of the measured absorbance over thatcalculated could be due to the presence of a small amount of absorbingimpurity, or some combination of small experimental errors.

[0346] The isolated material was found to be an active antifibrilantwhen it was orally administered to a dog by the inventors.

Example 21 Effect of Administration of BretyliumTosylate/Aspirin/Propranol on Ventricular Fibrillation Threshold

[0347] This example demonstrates the oral administration of abretylium/aspirin/propranolol composition and the corresponding effecton ventricular fibrillation threshold (VFT) and effective ventricularrefractory period (EVRP).

[0348] The experiment was conducted using a mongrel dog weighingapproximately 23 kg. The dog was anesthetized with isofluorine gas andrespired with a Harvard respirator using room air. The dog's chest wasopened via a midsternotomy to expose the heart and an electrode wasapplied to the surface of the right ventricle.

[0349] The ventricular fibrillation threshold was determined using aGrass Instruments Company constant current unit to initiate a gatedtrain of 60 Hz impulses of 1 millisecond duration. The current trainbegan immediately after ventricular activation and was sustained longenough to cover the vulnerable period during which ventricularfibrillation can be electrically induced. The ventricular stimulus beganat 3 milliamps and was increased in 3-4 milliamp steps until sustainedventricular fibrillation was induced (or until the maximum current of 50milliamps was applied.)

[0350] After the control VFT and EVRP were measured, a combinationcomprising bretylium tosylate, the sodium salt of acetylsalicylic acidand propranolol was orally administered via a stomach tube. First, about1 mg/kg of propranolol was pushed by a rod into the stomach tube andwashed into the stomach with 500 mg of bicarbonate dissolved in 50 mL ofwater. Immediately following, 15 mg/kg of a composition in capsule formcontaining an equimolar amount of bretylium tosylate and theacetylsalicylic acid was pushed by a rod into the stomach tube andwashed into the stomach with a liquid comprising sodium citrate, citricacid and aspirin in the form of a standard, commercially availableAlka-Seltzer tablet dissolved in 50 mL of water. VFT and EVRP were thenmeasured at various times following the administration. Heart rate andblood pressure were also measured throughout the experiment. Results ofthe VFT and EVRP measurements are shown in Table 6. Results of the heartrate and blood pressure measurements are shown in Table 7.

[0351] Generally, after 5 minutes, VFT almost doubled. After 30 minutesVFT was more than six times the control and VFT continued to increaseprogressively over time. After 120 minutes, the heart still could not befibrillated at 50 milliamps (the generator maximum). Therefore, thedog's left anterior descending coronary artery was occluded to attemptto induce ventricular fibrillation. Generally, coronary occlusionsignificantly reduces VFT or causes spontaneous ventricularfibrillation. However, despite 20 minutes of LAD occlusion, the heartcould still not be fibrillated at 50 milliamps. At 139 minutes, theocclusion was released, and again, no ventricular fibrillation orreperfusion ventricular fibrillation was observed for the following 30minutes (VFT was greater than 50 milliamps).

[0352] As seen in Table 7, cardiac hemodynamics (blood pressure andheart rate) remained very stable throughout the procedure. Generally,blood pressure falls during coronary artery occlusion; but, thecomposition prevented a deleterious effect, and in fact, improvedcardiac hemodynamics during the experiment. TABLE 6 Time afteradministration (min) VFT (mamp) EVRP (msec) −20 6 105 0 Administration 511 108 30 37 110 60 45 110 90 47 112 120 >50 112 124 LAD Ligated 139 >50112

[0353] TABLE 7 Time after Heart Rate Blood Pressure Administration (min)(beats per min) (Systolic/Diastolic) −20 100 136/98  0 100 136/98  5 100150/98  30 100 150/100 60 92 175/100 90 95 175/102 120 97 175/105 124 98175/108 139 98 170/100 146 95 155/105

Example 22 Preparation of a Bretylium/Propranolol Resuscitation Solution

[0354] This example demonstrates the preparation of a resuscitationsolution comprising a bretylium ion, aspirin and a β-receptor blocker.Such resuscitation solutions are suitable for administration to apatient suffering ventricular fibrillation.

[0355] The solution is prepared by dissolving bretylium tosylate (15mg/kg), acetylsalicylic acid (7.5 mg/kg), propranolol (0.5 mg/kg),meglumine (0.3 mmol/kg) and potassium gluconate (2 mmol/dose) in anaqueous solution of 5% glucose (70 mL). For producing a resuscitationsolution suitable for administration to an average (70 kg) human, thesolution contains bretylium tosylate (1.05 g), acetylsalicylic acid (525mg), propranolol (35 mg), meglumine (4095 mg) and potassium gluconate(468 mg) in 70 mL of an aqueous solution of 5% glucose.

Example 23 Preparation of a Bretylium/Metoprolol Resuscitation Solution

[0356] This example demonstrates the preparation of a resuscitationsolution comprising a bretylium ion, aspirin and a β-receptor blocker.Such resuscitation solutions are suitable for administration to apatient suffering ventricular fibrillation.

[0357] The solution is prepared by dissolving bretylium tosylate (15mg/kg), acetylsalicylic acid (7.5 mg/kg), metoprolol (0.5 mg/kg),meglumine (0.3 mmol/kg) and potassium gluconate (2 mmol/dose) in anaqueous solution of 5% glucose (70 mL). For producing a resuscitationsolution suitable for administration to an average (70 kg) human, thesolution contains bretylium tosylate (1.05 g), acetylsalicylic acid (525mg), metoprolol (35 mg), meglumine (4095 mg) and potassium gluconate(468 mg) in 70 mL of an aqueous solution of 5% glucose.

Example 24 Preparation of a Bretylium/Esmolol Resuscitation Solution

[0358] This example demonstrates the preparation of a resuscitationsolution comprising a bretylium ion, aspirin and a β-receptor blocker.Such resuscitation solutions are suitable for administration to apatient suffering ventricular fibrillation.

[0359] The solution is prepared by dissolving bretylium tosylate (15mg/kg), acetylsalicylic acid (7.5 mg/kg), esmolol (0.25 mg/kg),meglumine (0.3 mmol/kg) and potassium gluconate (2 mmol/dose) in anaqueous solution of 5% glucose (70 mL). For producing a resuscitationsolution suitable for administration to an average (70 kg) human, thesolution contains bretylium tosylate (1.05 g), acetylsalicylic acid (525mg), esmolol (17.5 mg), meglumine (4095 mg) and potassium gluconate (468mg) in 70 mL of an aqueous solution of 5% glucose.

Example 25 Preparation of a Bretylium/Propranolol Resuscitation Solution

[0360] This example demonstrates the preparation of a resuscitationsolution comprising a bretylium ion, aspirin and a β-receptor blocker.Such resuscitation solutions are suitable for administration to apatient suffering ventricular fibrillation.

[0361] The solution is prepared by dissolving bretylium tosylate (15mg/kg), acetylsalicylic acid (7.5 mg/kg), propranolol (0.5 mg/kg),meglumine (0.3 mmol/kg) and potassium gluconate (2 mmol/dose) in anaqueous solution of 5% glucose (70 mL). For producing a resuscitationsolution suitable for administration to an average (70 kg) human, thesolution contains bretylium tosylate (1.05 g), acetylsalicylic acid (525mg), propranolol (35 mg), meglumine (4095 mg) and potassium gluconate(468 mg) in 70 mL of an aqueous solution of 5% glucose.

[0362] The above description of the preferred embodiments and theaccompanying figures are intended only to acquaint others skilled in theart with the invention, its principles, and its practical application,so that others skilled in the art may adapt and apply the invention inits numerous forms, as may be best suited to the requirements of aparticular use. The present invention, therefore, is not limited to theabove embodiments, and may be variously modified.

[0363] All patent documents and other literature references cited inthis specification are incorporated herein by reference.measured in saidsubject prior to the administration of said pharmaceutical composition.

We claim:
 1. A pharmaceutical combination useful for preventing and/ortreating a cardiovascular condition, the pharmaceutical combinationcomprising: a bretylium cation or a source of a bretylium cation; anacetylsalicylate anion or a source of an acetylsalicylate anion; and aβ-receptor blocker or a source of a β-receptor blocker, saidacetylsalicylate anion comprising a compound of the structure:

wherein: R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl;R¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl; and saidbretylium cation or said source of a bretylium cation, saidacetylsalicylate anion or source of an acetylsalicylate anion, and saidβ-receptor blocker or said source of a β-receptor blocker together arepresent in said pharmaceutical combination in a therapeuticallyeffective amount.
 2. A pharmaceutical combination as set forth in claim1 wherein said combination comprises a pharmaceutical compositioncomprising: a bretylium cation, an acetylsalicylate anion and aβ-receptor blocker, said acetylsalicylate anion comprising a compound ofthe structure:

wherein: R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl;R¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl; and saidbretylium cation, said acetylsalicylate anion and said β-receptorblocker together are present in said pharmaceutical composition in atherapeutically effective amount.
 3. A pharmaceutical combination as setforth in claim 2 wherein the R¹⁷ substituent of the acetylsalicylateanion is hydrocarbyl and the R¹⁸ substituent of the acetylsalicylateanion is hydrogen.
 4. A pharmaceutical combination as set forth in claim2 wherein the combination comprises a pharmaceutical composition havinga molar ratio of acetylsalicylate anion to bretylium cation of fromabout 0.5 to about
 4. 5. A pharmaceutical combination as set forth inclaim 4 wherein the combination comprises a pharmaceutical compositionhaving a molar ratio of acetylsalicylate anion to bretylium cation offrom about 1 to about
 2. 6. A pharmaceutical combination as set forth inclaim 4 wherein the combination comprises a pharmaceutical compositionhaving a molar ratio of acetylsalicylate anion to bretylium cation offrom about 1.1 to about 1.5.
 7. A pharmaceutical combination as setforth in claim 2 wherein the combination comprises a pharmaceuticalcomposition comprising a β-receptor blocker selected from the groupconsisting of propranolol, atenolol, esmolol, metoprolol, labetalol,talinolol, timolol, carvedilol and acebutolol.
 8. A pharmaceuticalcombination as set forth in claim 6, wherein said β-receptor blockercomprises propranolol.
 9. A pharmaceutical combination as set forth inclaim 6, wherein said β-receptor blocker comprises metoprolol.
 10. Apharmaceutical combination as set forth in claim 6, wherein saidcombination comprises from about 0.01% to about 1.0% by weightβ-receptor blocker.
 11. A pharmaceutical combination as set forth inclaim 6, wherein said combination comprises a pharmaceutical compositioncomprising from about 10% to about 60% by weight bretylium cation, fromabout 5% to about 30% by weight acetylsalicylate anion, and from about0.01% to about 1.0% by weight β-receptor blocker.
 12. A pharmaceuticalcombination as set forth in claim 2, wherein when said pharmaceuticalcomposition is orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about fiveminutes after the administration of said pharmaceutical composition isat least about 25% higher than the electrical ventricular fibrillationthreshold measured in said subject prior to the administration of saidpharmaceutical composition.
 13. A pharmaceutical combination as setforth in claim 12, wherein when said pharmaceutical composition isorally administered to a subject, the electrical ventricularfibrillation threshold measured in said subject about five minutes afterthe administration of said pharmaceutical composition is at least about50% higher than the electrical ventricular fibrillation thresholdmeasured in said subject prior to the administration of saidpharmaceutical composition.
 14. A pharmaceutical combination as setforth in claim 12, wherein when said pharmaceutical composition isorally administered to a subject, the electrical ventricularfibrillation threshold measured in said subject about five minutes afterthe administration of said pharmaceutical composition is at least about75% higher than the electrical ventricular fibrillation thresholdmeasured in said subject prior to the administration of saidpharmaceutical composition.
 15. A pharmaceutical combination as setforth in claim 2, wherein when said pharmaceutical composition is orallyadministered to a subject, the electrical ventricular fibrillationthreshold measured in said subject about five minutes after theadministration of said pharmaceutical composition is about two timeshigher than the electrical ventricular fibrillation threshold measuredin said subject prior to the administration of said pharmaceuticalcomposition.
 16. A pharmaceutical combination as set forth in claim 2,wherein when said pharmaceutical composition is orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about 30 minutes after the administration of saidpharmaceutical composition is at least about two times higher than theelectrical ventricular fibrillation threshold measured in said subjectbefore the administration of said pharmaceutical composition.
 17. Apharmaceutical combination as set forth in claim 2, wherein when saidpharmaceutical composition is orally administered to a subject, theelectrical ventricular fibrillation threshold measured in said subjectabout 30 minutes after the administration of said pharmaceuticalcomposition is at least about four times higher than the electricalventricular fibrillation threshold measured in said subject before theadministration of said pharmaceutical composition.
 18. A pharmaceuticalcombination as set forth in claim 2, wherein when said pharmaceuticalcomposition is orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about 30minutes after the administration of said pharmaceutical composition isabout six times higher than the electrical ventricular fibrillationthreshold measured in said subject before the administration of saidpharmaceutical composition.
 19. A pharmaceutical combination as setforth in claim 2 further comprising an anti-hypotensive agent.
 20. Apharmaceutical combination as set forth in claim 19 wherein saidanti-hypotensive agent comprises epinephrine.
 21. A pharmaceuticalcombination as set forth in claim 19 wherein said anti-hypotensive agentcomprises a tricyclic anti-depressant compound.
 22. A pharmaceuticalcombination as set forth in claim 21 wherein said anti-hypotensive agentcomprises a tricyclic anti-depressant compound selected from the groupconsisting of protriptyline, mazindol, amitriptyline, nortriptyline anddesipramine.
 23. A pharmaceutical combination as set forth in claim 19,wherein said combination comprises a pharmaceutical compositioncomprising from about 0.01% to about 0.5% by weight anti-hypotensiveagent.
 24. A pharmaceutical combination as set forth in claim 2 whereinsaid composition further comprises a neutralizing agent.
 25. Apharmaceutical combination as set forth in claim 24 wherein saidneutralizing agent comprises a mono-, di-, or poly-amino sugar.
 26. Apharmaceutical combination as set forth in claim 25 wherein saidneutralizing agent comprises methyl glucamine.
 27. A pharmaceuticalcombination as set forth in claim 24, wherein said combination comprisesa pharmaceutical composition comprising from about 0.01% to about 70% byweight neutralizing agent.
 28. A pharmaceutical combination as set forthin claim 27, wherein said combination comprises a pharmaceuticalcomposition comprising from about 30% to about 70% by weightneutralizing agent.
 29. A pharmaceutical combination as set forth inclaim 2 wherein said composition further comprises a neutralizing agentand a buffering agent.
 30. A pharmaceutical combination as set forth inclaim 29 wherein said neutralizing agent comprises sodium bicarbonate orsodium citrate and said buffering agent comprises citric acid.
 31. Apharmaceutical combination as set forth in claim 2 wherein thecombination comprises a pharmaceutical composition suitable for oraladministration.
 32. A pharmaceutical combination as set forth in claim2, wherein said combination is in a form comprising a tablet or acapsule.
 33. A pharmaceutical combination as set forth in claim 2,wherein said combination is in a form comprising a solution orsuspension.
 34. A pharmaceutical combination as set forth in claim 2,wherein said combination is in a form suitable for administering viainjection.
 35. A pharmaceutical combination as set forth in claim 34,wherein said combination is suitable for intravenous or intramuscularinjection.
 36. A pharmaceutical combination as set forth in claim 34,wherein said combination further comprises a buffer.
 37. Apharmaceutical combination as set forth in claim 34, wherein saidcombination further comprises a bulking, dispersing, wetting orsuspending agent.
 38. A pharmaceutical combination as set forth in claim34, wherein said combination further comprises eplerenone.
 39. Apharmaceutical combination as set forth in claim 1 wherein saidcombination comprises a pharmaceutical kit comprising: a source of abretylium cation, a source of an acetylsalicylate anion and a source ofa β-receptor blocker, said acetylsalicylate anion comprising a compoundof the structure:

wherein: R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl;R¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl; and saidbretylium cation source, said acetylsalicylate anion source and saidβ-receptor blocker source together are present in said pharmaceuticalkit in a therapeutically effective amount.
 40. A pharmaceuticalcombination as set forth in claim 39 wherein the R¹⁷ substituent of theacetylsalicylate anion is hydrocarbyl and the R¹⁸ substituent of theacetylsalicylate anion is hydrogen.
 41. A pharmaceutical combination asset forth in claim 39 wherein the molar ratio of said acetylsalicylateanion to said bretylium cation is from about 0.5 to about
 4. 42. Apharmaceutical combination as set forth in claim 41 wherein the molarratio of said acetylsalicylate anion to said bretylium cation is fromabout 1 to about
 2. 43. A pharmaceutical combination as set forth inclaim 41 wherein the molar ratio of said acetylsalicylate anion to saidbretylium cation is from about 1.1 to about 1.5.
 44. A pharmaceuticalcombination as set forth in claim 39 wherein said β-receptor blocker isselected from the group consisting of propranolol, atenolol, esmolol,metoprolol, labetalol, talinolol, timolol, carvedilol and acebutolol.45. A pharmaceutical combination as set forth in claim 44, wherein saidβ-receptor blocker comprises propranolol.
 46. A pharmaceuticalcombination as set forth in claim 44, wherein said β-receptor blockercomprises metoprolol.
 47. A pharmaceutical combination as set forth inclaim 39, wherein said combination comprises from about 0.01% to about1.0% by weight β-receptor blocker.
 48. A pharmaceutical combination asset forth in claim 39, wherein when the components of saidpharmaceutical kit are orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about fiveminutes after the administration of the components of saidpharmaceutical kit is at least about 25% higher than the electricalventricular fibrillation threshold measured in said subject prior to theadministration of the components of said pharmaceutical kit.
 49. Apharmaceutical combination as set forth in claim 48, wherein when thecomponents of said pharmaceutical kit are orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about five minutes after the administration of thecomponents of said pharmaceutical kit is at least about 50% higher thanthe electrical ventricular fibrillation threshold measured in saidsubject prior to the administration of the components of saidpharmaceutical kit.
 50. A pharmaceutical combination as set forth inclaim 48, wherein when the components of said pharmaceutical kit areorally administered to a subject, the electrical ventricularfibrillation threshold measured in said subject about five minutes afterthe administration of the components of said pharmaceutical kit is atleast about 75% higher than the electrical ventricular fibrillationthreshold measured in said subject prior to the administration of thecomponents of said pharmaceutical kit.
 51. A pharmaceutical combinationas set forth in claim 39, wherein when the components of saidpharmaceutical kit are orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about fiveminutes after the administration of the components of saidpharmaceutical kit is about two times higher than the electricalventricular fibrillation threshold measured in said subject prior to theadministration of the components of said pharmaceutical kit.
 52. Apharmaceutical combination as set forth in claim 39, wherein when thecomponents of said pharmaceutical kit are orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about 30 minutes after the administration of the componentsof said pharmaceutical kit is at least about two times higher than theelectrical ventricular fibrillation threshold measured in said subjectbefore the administration of the components of said pharmaceutical kit.53. A pharmaceutical combination as set forth in claim 39, wherein whenthe components of said pharmaceutical kit are orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about 30 minutes after the administration of the componentsof said pharmaceutical kit is at least about four times higher than theelectrical ventricular fibrillation threshold measured in said subjectbefore the administration of the components of said pharmaceutical kit.54. A pharmaceutical combination as set forth in claim 39, wherein whenthe components of said pharmaceutical kit are orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about 30 minutes after the administration of the componentsof said pharmaceutical kit is about six times higher than the electricalventricular fibrillation threshold measured in said subject before theadministration of the components of said pharmaceutical kit.
 55. Apharmaceutical combination as set forth in claim 39 further comprising asource of an anti-hypotensive agent.
 56. A pharmaceutical combination asset forth in claim 55 wherein said anti-hypotensive agent comprisesepinephrine.
 57. A pharmaceutical combination as set forth in claim 55wherein said anti-hypotensive agent comprises a tricyclicanti-depressant compound.
 58. A pharmaceutical combination as set forthin claim 57 wherein said anti-hypotensive agent comprises a tricyclicanti-depressant compound selected from the group consisting ofprotriptyline, mazindol, amitriptyline, nortriptyline and desipramine.59. A pharmaceutical combination as set forth in claim 55, wherein saidcombination comprises from about 0.01% to about 0.5% by weightanti-hypotensive agent.
 60. A pharmaceutical combination as set forth inclaim 39 wherein said kit further comprises a source of a neutralizingagent.
 61. A pharmaceutical combination as set forth in claim 60 whereinsaid neutralizing agent comprises a mono-, di-, or poly-amino sugar. 62.A pharmaceutical combination as set forth in claim 61 wherein saidneutralizing agent comprises methyl glucamine.
 63. A pharmaceuticalcombination as set forth in claim 60, wherein said combination comprisesfrom about 0.01% to about 70% by weight neutralizing agent.
 64. Apharmaceutical combination as set forth in claim 63, wherein saidcombination comprises from about 30% to about 70% by weight neutralizingagent.
 65. A pharmaceutical combination as set forth in claim 39 whereinsaid kit further comprises a source of a neutralizing agent and a sourceof a buffering agent.
 66. A pharmaceutical combination as set forth inclaim 65 wherein said neutralizing agent comprises sodium bicarbonate orsodium citrate and said buffering agent comprises citric acid.
 67. Apharmaceutical combination as set forth in claim 66 wherein the sourceof said neutralizing agent and the source of said buffering agent are incombination and comprise a commercially available Alka Seltzer® tablet.68. A pharmaceutical combination as set forth in claim 39 wherein saidcombination comprises a pharmaceutical kit comprising at least 3separate unit dosages, said unit dosages being a unit dosage comprisingsaid source of said bretylium cation, a unit dosage comprising saidsource of said acetylsalicylate anion and a unit dosage comprising saidsource of said β-receptor blocker.
 69. A pharmaceutical combination asset forth in claim 39 wherein the source of said bretylium cationcomprises bretylium tosylate.
 70. A pharmaceutical combination usefulfor preventing and/or treating a cardiovascular condition, saidpharmaceutical combination comprising: a bretylium cation or a source ofa bretylium cation; acetylsalicylic acid or an alkali metal salt ofacetylsalicylic acid; and a β-receptor blocker or a source of aβ-receptor blocker, wherein: said pharmaceutical combination is suitablefor oral ingestion; and said bretylium cation or said source of abretylium cation, said acetylsalicylic acid or said alkali metal salt ofacetylsalicylic acid, and said β-receptor blocker or said source of aβ-receptor blocker together are present in said pharmaceuticalcomposition in a therapeutically effective amount.
 71. A pharmaceuticalcombination as set forth in claim 70 wherein the combination comprises apharmaceutical composition comprising: a bretylium cation,acetylsalicylic acid or an alkali metal salt of acetylsalicylic acid anda β-receptor blocker, wherein: said pharmaceutical composition issuitable for oral ingestion; and said bretylium cation, saidacetylsalicylic acid or alkali metal salt of acetylsalicylic acid andsaid β-receptor blocker together are present in said pharmaceuticalcomposition in a therapeutically effective amount.
 72. A pharmaceuticalcombination as set forth in claim 71 wherein the molar ratio of saidacetylsalicylic acid or alkali metal salt of acetylsalicylic acid tosaid bretylium cation is from about 0.5 to about
 4. 73. A pharmaceuticalcombination as set forth in claim 72 wherein the molar ratio of saidacetylsalicylic acid or alkali metal salt of acetylsalicylic acid tosaid bretylium cation is from about 1 to about
 2. 74. A pharmaceuticalcombination as set forth in claim 72 wherein the molar ratio of saidacetylsalicylic acid or alkali metal salt of acetylsalicylic acid tobretylium cation is from about 1.1 to about 1.5.
 75. A pharmaceuticalcombination as set forth in claim 71 wherein said β-receptor blocker isselected from the group consisting of propranolol, atenolol, esmolol,metoprolol, labetalol, talinolol, timolol, carvedilol and acebutolol.76. A pharmaceutical combination as set forth in claim 71, wherein saidβ-receptor blocker comprises propranolol.
 77. A pharmaceuticalcombination as set forth in claim 71, wherein said β-receptor blockercomprises metoprolol.
 78. A pharmaceutical combination as set forth inclaim 71, wherein said combination comprises from about 0.01% to about1.0% by weight β-receptor blocker.
 79. A pharmaceutical combination asset forth in claim 71, wherein said combination comprises apharmaceutical composition comprising from about 10% to about 60% byweight bretylium cation, from about 5% to about 30% by weightacetylsalicylic acid or alkali metal salt of acetylsalicylic acid, andfrom about 0.01% to about 1.0% by weight β-receptor blocker.
 80. Apharmaceutical combination as set forth in claim 71, wherein when saidpharmaceutical composition is orally administered to a subject, theelectrical ventricular fibrillation threshold measured in said subjectabout five minutes after the administration of said pharmaceuticalcomposition is at least about 25% higher than the electrical ventricularfibrillation threshold measured in said subject prior to theadministration of said pharmaceutical composition.
 81. A pharmaceuticalcombination as set forth in claim 80, wherein when the pharmaceuticalcomposition is orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about fiveminutes after the administration of said pharmaceutical composition isat least about 50% higher than the electrical ventricular fibrillationthreshold measured in said subject prior to the administration of saidpharmaceutical composition.
 82. A pharmaceutical combination as setforth in claim 80, wherein when said pharmaceutical composition isorally administered to a subject, the electrical ventricularfibrillation threshold measured in said subject about five minutes afterthe administration of said pharmaceutical composition is at least about75% higher than the electrical ventricular fibrillation thresholdmeasured in said subject prior to the administration of saidpharmaceutical composition.
 83. A pharmaceutical combination as setforth in claim 71, wherein when said pharmaceutical composition isorally administered to a subject, the electrical ventricularfibrillation threshold measured in said subject about five minutes afterthe administration of said pharmaceutical composition is about two timeshigher than the electrical ventricular fibrillation threshold measuredin said subject prior to the administration of said pharmaceuticalcomposition.
 84. A pharmaceutical combination as set forth in claim 71,wherein when said pharmaceutical composition is orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about 30 minutes after the administration of saidpharmaceutical composition is at least about two times higher than theelectrical ventricular fibrillation threshold measured in said subjectbefore the administration of said pharmaceutical composition.
 85. Apharmaceutical combination as set forth in claim 71, wherein when saidpharmaceutical composition is orally administered to a subject, theelectrical ventricular fibrillation threshold measured in said subjectabout 30 minutes after the administration of said pharmaceuticalcomposition is at least about four times higher than the electricalventricular fibrillation threshold measured in said subject before theadministration of said pharmaceutical composition.
 86. A pharmaceuticalcombination as set forth in claim 71, wherein when said pharmaceuticalcomposition is orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about 30minutes after the administration of said pharmaceutical composition isabout six times higher than the electrical ventricular fibrillationthreshold measured in said subject before the administration of saidpharmaceutical composition.
 87. A pharmaceutical combination as setforth in claim 71 further comprising an anti-hypotensive agent.
 88. Apharmaceutical combination as set forth in claim 87 wherein saidanti-hypotensive agent comprises epinephrine.
 89. A pharmaceuticalcombination as set forth in claim 87 wherein said anti-hypotensive agentcomprises a tricyclic anti-depressant compound.
 90. A pharmaceuticalcombination as set forth in claim 89 wherein said anti-hypotensive agentcomprises a tricyclic anti-depressant compound selected from the groupconsisting of protriptyline, mazindol, amitriptyline, nortriptyline anddesipramine.
 91. A pharmaceutical combination as set forth in claim 87,wherein said combination comprises a pharmaceutical compositioncomprising from about 0.01% to about 0.5% by weight anti-hypotensiveagent.
 92. A pharmaceutical combination as set forth in claim 71 whereinsaid composition further comprises a neutralizing agent.
 93. Apharmaceutical combination as set forth in claim 92 wherein saidneutralizing agent comprises a mono-, di-, or poly-amino sugar.
 94. Apharmaceutical combination as set forth in claim 93 wherein saidneutralizing agent comprises methyl glucamine.
 95. A pharmaceuticalcombination as set forth in claim 92, wherein said combination comprisesa pharmaceutical composition comprising from about 0.01% to about 70% byweight neutralizing agent.
 96. A pharmaceutical combination as set forthin claim 95, wherein said combination comprises a pharmaceuticalcomposition comprising from about 30% to about 70% by weightneutralizing agent.
 97. A pharmaceutical combination as set forth inclaim 71 wherein said composition further comprises a neutralizing agentand a buffering agent.
 98. A pharmaceutical combination as set forth inclaim 97 wherein said neutralizing agent comprises sodium bicarbonate orsodium citrate and said buffering agent comprises citric acid.
 99. Apharmaceutical combination as set forth in claim 71 wherein thecombination comprises a pharmaceutical composition suitable for oraladministration.
 100. A pharmaceutical combination as set forth in claim71, wherein said combination is in a form comprising a tablet or acapsule.
 101. A pharmaceutical combination as set forth in claim 71,wherein said combination is in a form comprising a solution orsuspension.
 102. A pharmaceutical combination as set forth in claim 71,wherein said combination is in a form suitable for administering viainjection.
 103. A pharmaceutical combination as set forth in claim 102,wherein said combination is suitable for intravenous or intramuscularinjection.
 104. A pharmaceutical combination as set forth in claim 102,wherein said combination further comprises a buffer.
 105. Apharmaceutical combination as set forth in claim 102, wherein saidcombination further comprises a bulking, dispersing, wetting orsuspending agent.
 106. A pharmaceutical combination as set forth inclaim 102, wherein said combination further comprises eplerenone.
 107. Apharmaceutical combination as set forth in claim 70 wherein saidcombination comprises a pharmaceutical kit comprising: a source of abretylium cation, acetylsalicylic acid or an alkali metal salt ofacetylsalicylic acid and a source of a β-receptor blocker, wherein: saidsource of said bretylium cation, said acetylsalicylic acid or alkalimetal salt of acetylsalicylic acid, and said source of said β-receptorblocker are, in combination, suitable for oral ingestion; and saidsource of said bretylium cation, said acetylsalicylic acid or alkalimetal salt of acetylsalicylic acid and said source of said β-receptorblocker are present in said kit in a therapeutically effective amount.108. A pharmaceutical combination as set forth in claim 107 wherein themolar ratio of said acetylsalicylic acid or alkali metal salt ofacetylsalicylic acid to said bretylium cation is from about 0.5 to about4.
 109. A pharmaceutical combination as set forth in claim 108 whereinthe molar ratio of said acetylsalicylic acid or alkali metal salt ofacetylsalicylic acid to said bretylium cation is from about 1 to about2.
 110. A pharmaceutical combination as set forth in claim 108 whereinthe molar ratio of acetylsalicylic acid or alkali metal salt ofacetylsalicylic acid to bretylium cation is from about 1.1 to about 1.5.111. A pharmaceutical combination as set forth in claim 107 wherein saidβ-receptor blocker is selected from the group consisting of propranolol,atenolol, esmolol, metoprolol, labetalol, talinolol, timolol, carvediloland acebutolol.
 112. A pharmaceutical combination as set forth in claim111 wherein said β-receptor blocker comprises propranolol.
 113. Apharmaceutical combination as set forth in claim 111 wherein saidβ-receptor blocker comprises metoprolol.
 114. A pharmaceuticalcombination as set forth in claim 107, wherein said combinationcomprises from about 0.01% to about 1.0% by weight β-receptor blocker.115. A pharmaceutical combination as set forth in claim 107, whereinwhen the components of said pharmaceutical kit are orally administeredto a subject, the electrical ventricular fibrillation threshold measuredin said subject about five minutes after the administration of thecomponents of said pharmaceutical kit is at least about 25% higher thanthe electrical ventricular fibrillation threshold measured in saidsubject prior to the administration of the components of saidpharmaceutical kit.
 116. A pharmaceutical combination as set forth inclaim 115, wherein when the components of said pharmaceutical kit areorally administered to a subject, the electrical ventricularfibrillation threshold measured in said subject about five minutes afterthe administration of the components of said pharmaceutical kit is atleast about 50% higher than the electrical ventricular fibrillationthreshold measured in said subject prior to the administration of thecomponents of said pharmaceutical kit.
 117. A pharmaceutical combinationas set forth in claim 115, wherein when the components of saidpharmaceutical kit are orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about fiveminutes after the administration of the components of saidpharmaceutical kit is at least about 75% higher than the electricalventricular fibrillation threshold measured in said subject prior to theadministration of the components of said pharmaceutical kit.
 118. Apharmaceutical combination as set forth in claim 107, wherein when thecomponents of said pharmaceutical kit are orally administered to asubject, the electrical ventricular fibrillation threshold measured insaid subject about five minutes after the administration of thecomponents of said pharmaceutical kit is about two times higher than theelectrical ventricular fibrillation threshold measured in said subjectprior to the administration of the components of said pharmaceuticalkit.
 119. A pharmaceutical combination as set forth in claim 107,wherein when the components of said pharmaceutical kit are orallyadministered to a subject, the electrical ventricular fibrillationthreshold measured in said subject about 30 minutes after theadministration of the components of said pharmaceutical kit is at leastabout two times higher than the electrical ventricular fibrillationthreshold measured in said subject before the administration of thecomponents of said pharmaceutical kit.
 120. A pharmaceutical combinationas set forth in claim 107, wherein when the components of saidpharmaceutical kit are orally administered to a subject, the electricalventricular fibrillation threshold measured in said subject about 30minutes after the administration of the components of saidpharmaceutical kit is at least about four times higher than theelectrical ventricular fibrillation threshold measured in said subjectbefore the administration of the components of said pharmaceutical kit.121. A pharmaceutical combination as set forth in claim 107, whereinwhen the components of said pharmaceutical kit are orally administeredto a subject, the electrical ventricular fibrillation threshold measuredin said subject about 30 minutes after the administration of thecomponents of said pharmaceutical kit is about six times higher than theelectrical ventricular fibrillation threshold measured in said subjectbefore the administration of the components of said pharmaceutical kit.122. A pharmaceutical combination as set forth in claim 107 furthercomprising a source of an anti-hypotensive agent.
 123. A pharmaceuticalcombination as set forth in claim 122 wherein said anti-hypotensiveagent comprises epinephrine.
 124. A pharmaceutical combination as setforth in claim 122 wherein said anti-hypotensive agent comprises atricyclic anti-depressant compound.
 125. A pharmaceutical combination asset forth in claim 124 wherein said anti-hypotensive agent comprises atricyclic anti-depressant compound selected from the group consisting ofprotriptyline, mazindol, amitriptyline, nortriptyline and desipramine.126. A pharmaceutical combination as set forth in claim 122, whereinsaid combination comprises from about 0.01% to about 0.5% by weightanti-hypotensive agent.
 127. A pharmaceutical combination as set forthin claim 107 wherein said pharmaceutical kit further comprises a sourceof a neutralizing agent.
 128. A pharmaceutical combination as set forthin claim 127 wherein said neutralizing agent comprises a mono-, di-, orpoly-amino sugar.
 129. A pharmaceutical combination as set forth inclaim 128 wherein said neutralizing agent comprises methyl glucamine.130. A pharmaceutical combination as set forth in claim 127, whereinsaid combination comprises from about 0.01% to about 70% by weightneutralizing agent.
 131. A pharmaceutical combination as set forth inclaim 130, wherein said combination comprises from about 30% to about70% by weight neutralizing agent.
 132. A pharmaceutical combination asset forth in claim 107 wherein said pharmaceutical kit further comprisesa source of a neutralizing agent and a source of a buffering agent. 133.A pharmaceutical combination as set forth in claim 132 wherein saidneutralizing agent comprises sodium bicarbonate or sodium citrate andsaid buffering agent comprises citric acid.
 134. A pharmaceuticalcombination as set forth in claim 132 wherein the source of saidneutralizing agent and the source of said buffering agent are incombination and comprise a commercially available Alka Seltzer® tablet.135. A pharmaceutical combination as set forth in claim 107, whereinsaid combination comprises at least 3 separate unit dosages, the unitdosages being a unit dosage comprising the source of said bretyliumcation, a unit dosage comprising said acetylsalicylic acid or alkalimetal salt of acetylsalicylic acid and a unit dosage comprising thesource of said β-receptor blocker.
 136. A pharmaceutical combination asset forth in claim 107 wherein the source of said bretylium cationcomprises bretylium tosylate.
 137. A pharmaceutical compositioncomprising from about 10% to about 40% by weight bretylium cation, fromabout 5% to about 40% by weight acetylsalicylate anion, and from about0.1% to about 1.0% by weight β-receptor blocker.
 138. A pharmaceuticalcomposition as set forth in claim 137, wherein said β-receptor blockeris selected from the group consisting of propranolol, atenolol, esmolol,metoprolol, labetalol, talinolol, timolol, carvedilol and acebutolol139. A pharmaceutical composition as set forth in claim 138 wherein saidβ-receptor blocker comprises propranolol.
 140. A pharmaceuticalcomposition as set forth in claim 138 wherein said β-receptor blockercomprises metoprolol.
 141. A pharmaceutical composition as set forth inclaim 137 further comprising from about 30% to about 75% by weightneutralizing agent.
 142. A pharmaceutical composition as set forth inclaim 141, wherein said neutralizing agent comprises a mono-, di-, orpoly-amino sugar.
 143. A pharmaceutical composition as set forth inclaim 142 wherein said neutralizing agent comprises methyl glucamine.144. A pharmaceutical composition comprising a bretylium cation, anacetylsalicylate anion, a β-receptor blocker and a neutralizing agent.145. A pharmaceutical composition as set forth in claim 144, whereinsaid β-receptor blocker is selected from the group consisting ofpropranolol, atenolol, esmolol, metoprolol, labetalol, talinolol,timolol, carvedilol and acebutolol.
 146. A pharmaceutical composition asset forth in claim 144 wherein said β-receptor blocker comprisespropranolol.
 147. A pharmaceutical composition as set forth in claim 144wherein said β-receptor blocker comprises metoprolol.
 148. Apharmaceutical composition as set forth in claim 145, wherein saidneutralizing agent comprises a mono-, di-, or poly-amino sugar.
 149. Apharmaceutical composition as set forth in claim 148 wherein saidneutralizing agent comprises methyl glucamine.
 150. A pharmaceuticalcomposition as set forth in claim 144, wherein said composition is in aform comprising a solution or a suspension.
 151. A pharmaceuticalcomposition as set forth in claim 150, wherein said composition is in aform suitable for administration as an emergency resuscitation solutionfor treating sudden cardiac arrest.
 152. A method for treating suddencardiac arrest in a human or animal patient, the method comprisingadministering a pharmaceutical composition of claim 144 to a subject inneed thereof.
 153. A method as set forth in claim 152, wherein saidpharmaceutical composition comprises a bretylium cation, anacetylsalicylate anion, propranolol and methyl glucamine.
 154. A methodas set forth in claim 152, wherein said pharmaceutical compositioncomprises a bretylium cation, an acetylsalicylate anion, metoprolol andmethyl glucamine.
 155. A method for preventing and/or treating acardiovascular condition, said method comprising orally administering apharmaceutical combination of claim 1 to a subject in need thereof. 156.A method as set forth in claim 155 wherein said pharmaceuticalcombination comprises a pharmaceutical composition comprising: abretylium cation, an acetylsalicylate anion and a β-receptor blocker,said acetylsalicylate anion comprising a compound of the structure:

wherein: R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl;R¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl; and saidbretylium cation, said acetylsalicylate anion and said β-receptorblocker together are present in said pharmaceutical composition in atherapeutically effective amount.
 157. A method as set forth in claim155, wherein said pharmaceutical combination comprises a pharmaceuticalkit and said method comprises administering the components of saidpharmaceutical kit to a subject in need thereof, said pharmaceutical kitcomprising: a source of a bretylium cation, a source of anacetylsalicylate anion and a source of a β-receptor blocker, saidacetylsalicylate anion comprising a compound of the structure:

wherein: R¹⁷ is independently hydrocarbyl or substituted hydrocarbyl;R¹⁸ is hydrogen, hydrocarbyl or substituted hydrocarbyl; and saidbretylium cation source, said acetylsalicylate anion source and saidβ-receptor blocker source together are present in said pharmaceuticalkit in a therapeutically effective amount.
 158. A method as set forth inclaim 155, wherein said pharmaceutical combination is administered to:(1) prevent sudden cardiac death; (2) prevent and/or treat myocardialinfarction; (3) prevent and/or treat congestive heart failure; (4)prevent and/or treat ventricular fibrillation; (5) prevent and/or treatventricular arrhythmia; (6) prevent and/or treat ventriculartachycardia; (7) prevent and/or treat ventricular premature heartbeats;(8) prevent and/or treat atrioventricular dissociation; (9) preventand/or treat multifocal ectopic beats; (10) prevent and/or treatpremature ventricular extrasystoles; (11) prevent and/or treat bigeminalrhythm; (12) prevent and/or treat trigeminal rhythm; (13) prevent and/ortreat angina pectoris; (14) prevent and/or treat coronary insufficiency;(15) prevent and/or treat sympathetically induced pain; (16) restoreand/or maintain normal sinus rhythm; (17) increase the effectiveventricular refractory period; (18) increase the sinus automaticitytransiently; (19) prolong the Purkinje action potential duration; (20)induce post-ganglionic sympathetic blockade; (21) block the sympatheticnervous system; (22) reduce vascular impedance; (23) increase theelectrical ventricular fibrillation threshold; (24) prolong the actionpotential duration of cardiac cells; and/or (25) prevent or treatcongestive heart failure or coronary spasm.
 159. A method as set forthin claim 155 wherein said pharmaceutical combination is administered toprevent and/or treat atrial arrhythmia.
 160. A method as set forth inclaim 155, wherein said pharmaceutical combination is administered toprevent and/or treat atrial fibrillation.
 161. A method as set forth inclaim 160 wherein said combination is administered prior to theapplication of an external anti-defibrillatory shock.
 162. A method asset forth in claim 155 wherein said pharmaceutical combination isadministered to prevent and/or treat atrial tachycardia.
 163. A methodas set forth in claim 155 wherein said pharmaceutical combination isadministered to a human.
 164. A method for preventing and/or treating acardiovascular condition, said method comprising orally administering apharmaceutical combination of claim 70 to a subject in need thereof.165. A method as set forth in claim 164, wherein the pharmaceuticalcombination comprises a pharmaceutical composition comprising: abretylium cation, acetylsalicylic acid or an alkali metal salt ofacetylsalicylic acid and a β-receptor blocker, wherein: saidpharmaceutical composition is suitable for oral ingestion; and saidbretylium cation, said acetylsalicylic acid or alkali metal salt ofacetylsalicylic acid and said β-receptor blocker together are present insaid pharmaceutical composition in a therapeutically effective amount.166. A method as set forth in claim 164, wherein said pharmaceuticalcombination comprises a pharmaceutical kit comprising: a source of abretylium cation, acetylsalicylic acid or an alkali metal salt ofacetylsalicylic acid and a source of a β-receptor blocker, wherein: saidsource of said bretylium cation, said acetylsalicylic acid or alkalimetal salt of acetylsalicylic acid, and said source of said β-receptorblocker are, in combination, suitable for oral ingestion; and saidsource of said bretylium cation, said acetylsalicylic acid or alkalimetal salt of acetylsalicylic acid and said source of said β-receptorblocker are present in said kit in a therapeutically effective amount.167. A method as set forth in claim 164, wherein said pharmaceuticalcombination is administered to: (1) prevent sudden cardiac death; (2)prevent and/or treat myocardial infarction; (3) prevent and/or treatcongestive heart failure; (4) prevent and/or treat ventricularfibrillation; (5) prevent and/or treat ventricular arrhythmia; (6)prevent and/or treat ventricular tachycardia; (7) prevent and/or treatventricular premature heartbeats; (8) prevent and/or treatatrioventricular dissociation; (9) prevent and/or treat multifocalectopic beats; (10) prevent and/or treat premature ventricularextrasystoles; (11) prevent and/or treat bigeminal rhythm; (12) preventand/or treat trigeminal rhythm; (13) prevent and/or treat anginapectoris; (14) prevent and/or treat coronary insufficiency; (15) preventand/or treat sympathetically induced pain; (16) restore and/or maintainnormal sinus rhythm; (17) increase the effective ventricular refractoryperiod; (18) increase the sinus automaticity transiently; (19) prolongthe Purkinje action potential duration; (20) induce post-ganglionicsympathetic blockade; (21) block the sympathetic nervous system; (22)reduce vascular impedance; (23) increase the electrical ventricularfibrillation threshold; (24) prolong the action potential duration ofcardiac cells; and/or (25) prevent or treat congestive heart failure orcoronary spasm.
 168. A method as set forth in claim 164 wherein saidpharmaceutical combination is administered to prevent and/or treatatrial arrhythmia.
 169. A method as set forth in claim 164, wherein saidpharmaceutical combination is administered to prevent and/or treatatrial fibrillation.
 170. A method as set forth in claim 169 whereinsaid combination is administered prior to the application of an externalanti-defibrillatory shock.
 171. A method as set forth in claim 164wherein said pharmaceutical combination is administered to preventand/or treat atrial tachycardia.
 172. A method as set forth in claim 164wherein said pharmaceutical combination is administered to a human. 173.A method for preventing and/or treating a cardiovascular condition, saidmethod comprising orally administering a pharmaceutical composition ofclaim 137 to a subject in need thereof.
 174. A method as set forth inclaim 173, wherein said pharmaceutical composition is administered to:(1) prevent sudden cardiac death; (2) prevent and/or treat myocardialinfarction; (3) prevent and/or treat congestive heart failure; (4)prevent and/or treat ventricular fibrillation; (5) prevent and/or treatventricular arrhythmia; (6) prevent and/or treat ventriculartachycardia; (7) prevent and/or treat ventricular premature heartbeats;(8) prevent and/or treat atrioventricular dissociation; (9) preventand/or treat multifocal ectopic beats; (10) prevent and/or treatpremature ventricular extrasystoles; (11) prevent and/or treat bigeminalrhythm; (12) prevent and/or treat trigeminal rhythm; (13) prevent and/ortreat angina pectoris; (14) prevent and/or treat coronary insufficiency;(15) prevent and/or treat sympathetically induced pain; (16) restoreand/or maintain normal sinus rhythm; (17) increase the effectiveventricular refractory period; (18) increase the sinus automaticitytransiently; (19) prolong the Purkinje action potential duration; (20)induce post-ganglionic sympathetic blockade; (21) block the sympatheticnervous system; (22) reduce vascular impedance; (23) increase theelectrical ventricular fibrillation threshold; (24) prolong the actionpotential duration of cardiac cells; and/or (25) prevent or treatcongestive heart failure or coronary spasm.
 175. A method as set forthin claim 173 wherein said pharmaceutical combination is administered toprevent and/or treat atrial arrhythmia.
 176. A method as set forth inclaim 175, wherein said pharmaceutical combination is administered toprevent and/or treat atrial fibrillation.
 177. A method as set forth inclaim 176 wherein said combination is administered prior to theapplication of an external anti-defibrillatory shock.
 178. A method asset forth in claim 173 wherein said combination is administered prior tothrombolitic therapy.
 179. A method as set forth in claim 173 whereinsaid pharmaceutical combination is administered to prevent and/or treatatrial tachycardia.
 180. A method as set forth in claim 173 wherein saidpharmaceutical combination is administered to treat acute myocardialinfarction.
 181. A method as set forth in claim 173 wherein saidpharmaceutical combination is administered to a human.
 182. Apharmaceutical combination as set forth in claim 1, wherein saidcombination further comprises bethanidine sulfate.
 183. A method fortreating angina pectoris in a human or animal patient, said methodcomprising administering a pharmaceutical combination of claim 182 to asubject in need thereof.
 184. A method for treating and/or preventingshock, the method comprising administering a pharmaceutical combinationcomprising a bretylium cation or a source of a bretylium cation, afacilitating anion or a source of a facilitating anion, and ananti-hypotensive agent and/or a β-receptor blocker or a source of ananti-hypotensive agent and/or a β-receptor blocker to a human or animalpatient in need thereof, wherein: said facilitating anion is lesshydrophilic than a tosylate anion; and said bretylium cation or saidsource of a bretylium cation, said facilitating anion or said source ofa facilitating anion, and said anti-hypotensive agent and/or saidβ-receptor blocker or said source of an anti-hypotensive agent and/or aβ-receptor blocker together are present in said pharmaceuticalcombination in a therapeutically effective amount.
 185. A method as setforth in claim 184 wherein said pharmaceutical combination isadministered for the treatment and/or prevention of septic shock,hemorrhagic shock, cardiogenic shock or hypovolemic shock.